CGAS_HUMAN
ID CGAS_HUMAN Reviewed; 522 AA.
AC Q8N884; L0L2J9; Q14CV6; Q32NC9; Q5SWL0; Q5SWL1; Q96E45;
DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 2.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Cyclic GMP-AMP synthase {ECO:0000303|PubMed:23258413};
DE Short=cGAMP synthase {ECO:0000303|PubMed:23258413};
DE Short=cGAS {ECO:0000303|PubMed:23258413};
DE Short=h-cGAS {ECO:0000303|PubMed:23258413};
DE EC=2.7.7.86 {ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:23707061, ECO:0000269|PubMed:23722159, ECO:0000269|PubMed:25131990, ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30799039};
DE AltName: Full=2'3'-cGAMP synthase {ECO:0000303|PubMed:23258413};
DE AltName: Full=Mab-21 domain-containing protein 1;
GN Name=CGAS {ECO:0000303|PubMed:23258413, ECO:0000312|HGNC:HGNC:21367};
GN Synonyms=C6orf150 {ECO:0000312|HGNC:HGNC:21367},
GN MB21D1 {ECO:0000312|HGNC:HGNC:21367};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, ACTIVITY
RP REGULATION, DNA-BINDING, IDENTIFICATION BY MASS SPECTROMETRY, SUBCELLULAR
RP LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=23258413; DOI=10.1126/science.1232458;
RA Sun L., Wu J., Du F., Chen X., Chen Z.J.;
RT "Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type
RT I interferon pathway.";
RL Science 339:786-791(2013).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ASN-35.
RC TISSUE=Spleen;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=14574404; DOI=10.1038/nature02055;
RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L.,
RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R.,
RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D.,
RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H.,
RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V.,
RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J.,
RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E.,
RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J.,
RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J.,
RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C.,
RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A.,
RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R.,
RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M.,
RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K.,
RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R.,
RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M.,
RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A.,
RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L.,
RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I.,
RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y.,
RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E.,
RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A.,
RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W.,
RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M.,
RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J.,
RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M.,
RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I.,
RA Rogers J., Beck S.;
RT "The DNA sequence and analysis of human chromosome 6.";
RL Nature 425:805-811(2003).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP ASN-35 AND HIS-261.
RC TISSUE=Brain, Prostate, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-7 AND LYS-414, AND IDENTIFICATION
RP BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C.,
RA Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [6]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-143, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [7]
RP FUNCTION, AND INDUCTION.
RX PubMed=21478870; DOI=10.1038/nature09907;
RA Schoggins J.W., Wilson S.J., Panis M., Murphy M.Y., Jones C.T.,
RA Bieniasz P., Rice C.M.;
RT "A diverse range of gene products are effectors of the type I interferon
RT antiviral response.";
RL Nature 472:481-485(2011).
RN [8]
RP FUNCTION.
RX PubMed=23707065; DOI=10.1016/j.celrep.2013.05.009;
RA Diner E.J., Burdette D.L., Wilson S.C., Monroe K.M., Kellenberger C.A.,
RA Hyodo M., Hayakawa Y., Hammond M.C., Vance R.E.;
RT "The innate immune DNA sensor cGAS produces a noncanonical cyclic
RT dinucleotide that activates human STING.";
RL Cell Rep. 3:1355-1361(2013).
RN [9]
RP FUNCTION.
RX PubMed=24269171; DOI=10.1016/j.immuni.2013.11.002;
RA Lahaye X., Satoh T., Gentili M., Cerboni S., Conrad C., Hurbain I.,
RA El Marjou A., Lacabaratz C., Lelievre J.D., Manel N.;
RT "The capsids of HIV-1 and HIV-2 determine immune detection of the viral
RT cDNA by the innate sensor cGAS in dendritic cells.";
RL Immunity 39:1132-1142(2013).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LYS-173; LEU-174; ARG-176;
RP 212-GLY-SER-213; 225-GLU--ASP-227; 396-CYS-CYS-397; LYS-407 AND LYS-411.
RX PubMed=23722159; DOI=10.1038/nature12305;
RA Civril F., Deimling T., de Oliveira Mann C.C., Ablasser A., Moldt M.,
RA Witte G., Hornung V., Hopfner K.P.;
RT "Structural mechanism of cytosolic DNA sensing by cGAS.";
RL Nature 498:332-337(2013).
RN [11]
RP FUNCTION.
RX PubMed=24077100; DOI=10.1038/nature12640;
RA Ablasser A., Schmid-Burgk J.L., Hemmerling I., Horvath G.L., Schmidt T.,
RA Latz E., Hornung V.;
RT "Cell intrinsic immunity spreads to bystander cells via the intercellular
RT transfer of cGAMP.";
RL Nature 503:530-534(2013).
RN [12]
RP FUNCTION.
RX PubMed=23929945; DOI=10.1126/science.1240933;
RA Gao D., Wu J., Wu Y.T., Du F., Aroh C., Yan N., Sun L., Chen Z.J.;
RT "Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other
RT retroviruses.";
RL Science 341:903-906(2013).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF THR-211; ARG-376 AND
RP TYR-436.
RX PubMed=25131990; DOI=10.1016/j.cell.2014.07.028;
RA Kranzusch P.J., Lee A.S., Wilson S.C., Solovykh M.S., Vance R.E.,
RA Berger J.M., Doudna J.A.;
RT "Structure-guided reprogramming of human cGAS dinucleotide linkage
RT specificity.";
RL Cell 158:1011-1021(2014).
RN [14]
RP FUNCTION, AND INTERACTION WITH PQBP1.
RX PubMed=26046437; DOI=10.1016/j.cell.2015.04.050;
RA Yoh S.M., Schneider M., Seifried J., Soonthornvacharin S., Akleh R.E.,
RA Olivieri K.C., De Jesus P.D., Ruan C., de Castro E., Ruiz P.A.,
RA Germanaud D., des Portes V., Garcia-Sastre A., Koenig R., Chanda S.K.;
RT "PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-
RT 1.";
RL Cell 161:1293-1305(2015).
RN [15]
RP INTERACTION WITH HHV-8 PROTEIN ORF52 (MICROBIAL INFECTION).
RX PubMed=26320998; DOI=10.1016/j.chom.2015.07.015;
RA Wu J.J., Li W., Shao Y., Avey D., Fu B., Gillen J., Hand T., Ma S., Liu X.,
RA Miley W., Konrad A., Neipel F., Stuerzl M., Whitby D., Li H., Zhu F.;
RT "Inhibition of cGAS DNA Sensing by a Herpesvirus Virion Protein.";
RL Cell Host Microbe 18:333-344(2015).
RN [16]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=26048138; DOI=10.1016/j.chom.2015.05.003;
RA Wassermann R., Gulen M.F., Sala C., Perin S.G., Lou Y., Rybniker J.,
RA Schmid-Burgk J.L., Schmidt T., Hornung V., Cole S.T., Ablasser A.;
RT "Mycobacterium tuberculosis differentially activates cGAS- and
RT inflammasome-dependent intracellular immune responses through ESX-1.";
RL Cell Host Microbe 17:799-810(2015).
RN [17]
RP PHOSPHORYLATION AT SER-305, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP SER-305.
RX PubMed=26440888; DOI=10.1016/j.celrep.2015.09.007;
RA Seo G.J., Yang A., Tan B., Kim S., Liang Q., Choi Y., Yuan W., Feng P.,
RA Park H.S., Jung J.U.;
RT "Akt kinase-mediated checkpoint of cGAS DNA sensing pathway.";
RL Cell Rep. 13:440-449(2015).
RN [18]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=26300263; DOI=10.1016/j.molcel.2015.07.022;
RA Kranzusch P.J., Wilson S.C., Lee A.S., Berger J.M., Doudna J.A.,
RA Vance R.E.;
RT "Ancient origin of cGAS-STING reveals mechanism of universal 2',3' cGAMP
RT signaling.";
RL Mol. Cell 59:891-903(2015).
RN [19]
RP FUNCTION, AND MUTAGENESIS OF 225-GLU--ASP-227.
RX PubMed=26229115; DOI=10.1126/science.aab3628;
RA Gentili M., Kowal J., Tkach M., Satoh T., Lahaye X., Conrad C., Boyron M.,
RA Lombard B., Durand S., Kroemer G., Loew D., Dalod M., Thery C., Manel N.;
RT "Transmission of innate immune signaling by packaging of cGAMP in viral
RT particles.";
RL Science 349:1232-1236(2015).
RN [20]
RP SUMOYLATION AT LYS-231 AND LYS-479, UBIQUITINATION AT LYS-285 AND LYS-479,
RP AND MUTAGENESIS OF LYS-231 AND LYS-479.
RX PubMed=27637147; DOI=10.1016/j.immuni.2016.08.014;
RA Hu M.M., Yang Q., Xie X.Q., Liao C.Y., Lin H., Liu T.T., Yin L., Shu H.B.;
RT "Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor
RT STING to regulate the kinetics of response to DNA virus.";
RL Immunity 45:555-569(2016).
RN [21]
RP UBIQUITINATION AT LYS-414, INTERACTION WITH TRIM14, AND MUTAGENESIS OF
RP LYS-414.
RX PubMed=27666593; DOI=10.1016/j.molcel.2016.08.025;
RA Chen M., Meng Q., Qin Y., Liang P., Tan P., He L., Zhou Y., Chen Y.,
RA Huang J., Wang R.F., Cui J.;
RT "TRIM14 inhibits cGAS degradation mediated by selective autophagy receptor
RT p62 to promote innate immune responses.";
RL Mol. Cell 64:105-119(2016).
RN [22]
RP FUNCTION, AND DOMAIN.
RX PubMed=28214358; DOI=10.1002/1873-3468.12598;
RA Lee A., Park E.B., Lee J., Choi B.S., Kang S.J.;
RT "The N terminus of cGAS de-oligomerizes the cGAS:DNA complex and lifts the
RT DNA size restriction of core-cGAS activity.";
RL FEBS Lett. 591:954-961(2017).
RN [23]
RP FUNCTION, CLEAVAGE, ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF ASP-33;
RP ASP-67; ASP-90; ASP-95; ASP-140 AND ASP-157.
RX PubMed=28314590; DOI=10.1016/j.immuni.2017.02.011;
RA Wang Y., Ning X., Gao P., Wu S., Sha M., Lv M., Zhou X., Gao J., Fang R.,
RA Meng G., Su X., Jiang Z.;
RT "Inflammasome activation triggers caspase-1-mediated cleavage of cGAS to
RT regulate responses to DNA virus infection.";
RL Immunity 46:393-404(2017).
RN [24]
RP FUNCTION, DNA-BINDING, DOMAIN, AND MONOMER.
RX PubMed=28363908; DOI=10.4049/jimmunol.1601909;
RA Tao J., Zhang X.W., Jin J., Du X.X., Lian T., Yang J., Zhou X., Jiang Z.,
RA Su X.D.;
RT "Nonspecific DNA Binding of cGAS N Terminus Promotes cGAS Activation.";
RL J. Immunol. 198:3627-3636(2017).
RN [25]
RP FUNCTION.
RX PubMed=28738408; DOI=10.1038/nature23449;
RA Mackenzie K.J., Carroll P., Martin C.A., Murina O., Fluteau A.,
RA Simpson D.J., Olova N., Sutcliffe H., Rainger J.K., Leitch A., Osborn R.T.,
RA Wheeler A.P., Nowotny M., Gilbert N., Chandra T., Reijns M.A.M.,
RA Jackson A.P.;
RT "cGAS surveillance of micronuclei links genome instability to innate
RT immunity.";
RL Nature 548:461-465(2017).
RN [26]
RP FUNCTION.
RX PubMed=28759889; DOI=10.1038/nature23470;
RA Harding S.M., Benci J.L., Irianto J., Discher D.E., Minn A.J.,
RA Greenberg R.A.;
RT "Mitotic progression following DNA damage enables pattern recognition
RT within micronuclei.";
RL Nature 548:466-470(2017).
RN [27]
RP UBIQUITINATION AT LYS-173 AND LYS-384, ACTIVITY REGULATION, AND MUTAGENESIS
RP OF LYS-173 AND LYS-384.
RX PubMed=28273161; DOI=10.1371/journal.ppat.1006264;
RA Wang Q., Huang L., Hong Z., Lv Z., Mao Z., Tang Y., Kong X., Li S., Cui Y.,
RA Liu H., Zhang L., Zhang X., Jiang L., Wang C., Zhou Q.;
RT "The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune
RT response.";
RL PLoS Pathog. 13:e1006264-e1006264(2017).
RN [28]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=30270045; DOI=10.1016/j.cell.2018.08.062;
RA Lahaye X., Gentili M., Silvin A., Conrad C., Picard L., Jouve M., Zueva E.,
RA Maurin M., Nadalin F., Knott G.J., Zhao B., Du F., Rio M., Amiel J.,
RA Fox A.H., Li P., Etienne L., Bond C.S., Colleaux L., Manel N.;
RT "NONO detects the nuclear HIV capsid to promote cGAS-mediated innate immune
RT activation.";
RL Cell 175:488-501(2018).
RN [29]
RP UBIQUITINATION.
RX PubMed=29760876; DOI=10.1186/s13578-018-0233-3;
RA Liu Z.S., Zhang Z.Y., Cai H., Zhao M., Mao J., Dai J., Xia T., Zhang X.M.,
RA Li T.;
RT "RINCK-mediated monoubiquitination of cGAS promotes antiviral innate immune
RT responses.";
RL Cell Biosci. 8:35-35(2018).
RN [30]
RP INTERACTION WITH CYTOMEGALOVIRUS PROTEIN UL31 (MICROBIAL INFECTION), AND
RP SUBCELLULAR LOCATION.
RX PubMed=29937271; DOI=10.1016/j.chom.2018.05.007;
RA Huang Z.F., Zou H.M., Liao B.W., Zhang H.Y., Yang Y., Fu Y.Z., Wang S.Y.,
RA Luo M.H., Wang Y.Y.;
RT "Human Cytomegalovirus Protein UL31 Inhibits DNA Sensing of cGAS to Mediate
RT Immune Evasion.";
RL Cell Host Microbe 24:69-80(2018).
RN [31]
RP INTERACTION WITH HERPES SIMPLEX VIRUS 1 PROTEIN UL37 (MICROBIAL INFECTION),
RP DEAMIDATION AT ASN-210; ASN-389; GLN-451 AND GLN-454, AND MUTAGENESIS OF
RP ASN-210.
RX PubMed=30092200; DOI=10.1016/j.chom.2018.07.004;
RA Zhang J., Zhao J., Xu S., Li J., He S., Zeng Y., Xie L., Xie N., Liu T.,
RA Lee K., Seo G.J., Chen L., Stabell A.C., Xia Z., Sawyer S.L., Jung J.,
RA Huang C., Feng P.;
RT "Species-Specific Deamidation of cGAS by Herpes Simplex Virus UL37 Protein
RT Facilitates Viral Replication.";
RL Cell Host Microbe 24:234-248(2018).
RN [32]
RP INTERACTION WITH HERPES SIMPLEX VIRUS 1 PROTEIN UL49/VP22 (MICROBIAL
RP INFECTION).
RX PubMed=29793952; DOI=10.1128/jvi.00841-18;
RA Huang J., You H., Su C., Li Y., Chen S., Zheng C.;
RT "Herpes simplex virus 1 tegument protein VP22 abrogates cGAS/STING-mediated
RT antiviral innate immunity.";
RL J. Virol. 92:0-0(2018).
RN [33]
RP FUNCTION, SUBCELLULAR LOCATION, PHOSPHORYLATION AT TYR-215, INTERACTION
RP WITH PARP1, AND MUTAGENESIS OF 171-LYS--LEU-174; 210-ASN--TYR-214; TYR-215;
RP 225-GLU--ASP-227; 295-ASP--SER-305; ASP-319; LYS-384 AND LYS-407.
RX PubMed=30356214; DOI=10.1038/s41586-018-0629-6;
RA Liu H., Zhang H., Wu X., Ma D., Wu J., Wang L., Jiang Y., Fei Y., Zhu C.,
RA Tan R., Jungblut P., Pei G., Dorhoi A., Yan Q., Zhang F., Zheng R., Liu S.,
RA Liang H., Liu Z., Yang H., Chen J., Wang P., Tang T., Peng W., Hu Z.,
RA Xu Z., Huang X., Wang J., Li H., Zhou Y., Liu F., Yan D., Kaufmann S.H.E.,
RA Chen C., Mao Z., Ge B.;
RT "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.";
RL Nature 563:131-136(2018).
RN [34]
RP UBIQUITINATION.
RX PubMed=29426904; DOI=10.1038/s41467-018-02936-3;
RA Seo G.J., Kim C., Shin W.J., Sklan E.H., Eoh H., Jung J.U.;
RT "TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing.";
RL Nat. Commun. 9:613-613(2018).
RN [35]
RP INTERACTION WITH ZCCHC3.
RX PubMed=30135424; DOI=10.1038/s41467-018-05559-w;
RA Lian H., Wei J., Zang R., Ye W., Yang Q., Zhang X.N., Chen Y.D., Fu Y.Z.,
RA Hu M.M., Lei C.Q., Luo W.W., Li S., Shu H.B.;
RT "ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune
RT response.";
RL Nat. Commun. 9:3349-3349(2018).
RN [36]
RP INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL83 (MICROBIAL INFECTION),
RP AND SUBCELLULAR LOCATION.
RX PubMed=29263269; DOI=10.1128/jvi.01774-17;
RA Biolatti M., Dell'Oste V., Pautasso S., Gugliesi F., von Einem J.,
RA Krapp C., Jakobsen M.R., Borgogna C., Gariglio M., De Andrea M.,
RA Landolfo S.;
RT "Human Cytomegalovirus Tegument Protein pp65 (pUL83) Dampens Type I
RT Interferon Production by Inactivating the DNA Sensor cGAS without Affecting
RT STING.";
RL J. Virol. 92:0-0(2018).
RN [37]
RP FUNCTION, ACTIVITY REGULATION, CATALYTIC ACTIVITY, COFACTOR, AND DOMAIN.
RX PubMed=29976794; DOI=10.1126/science.aat1022;
RA Du M., Chen Z.J.;
RT "DNA-induced liquid phase condensation of cGAS activates innate immune
RT signaling.";
RL Science 361:704-709(2018).
RN [38]
RP SUBCELLULAR LOCATION, LIPID-BINDING, AND MUTAGENESIS OF 71-ARG--ARG-75 AND
RP 396-CYS-CYS-397.
RX PubMed=30827685; DOI=10.1016/j.cell.2019.01.049;
RA Barnett K.C., Coronas-Serna J.M., Zhou W., Ernandes M.J., Cao A.,
RA Kranzusch P.J., Kagan J.C.;
RT "Phosphoinositide interactions position cGAS at the plasma membrane to
RT ensure efficient distinction between self- and viral DNA.";
RL Cell 176:1432-1446(2019).
RN [39]
RP ACETYLATION AT LYS-7; LYS-50; LYS-384; LYS-392; LYS-394 AND LYS-414,
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, SUBUNIT, AND
RP MUTAGENESIS OF LYS-7; LYS-50; LYS-384; LYS-392; LYS-394 AND LYS-414.
RX PubMed=30799039; DOI=10.1016/j.cell.2019.01.016;
RA Dai J., Huang Y.J., He X., Zhao M., Wang X., Liu Z.S., Xue W., Cai H.,
RA Zhan X.Y., Huang S.Y., He K., Wang H., Wang N., Sang Z., Li T., Han Q.Y.,
RA Mao J., Diao X., Song N., Chen Y., Li W.H., Man J.H., Li A.L., Zhou T.,
RA Liu Z.G., Zhang X.M., Li T.;
RT "Acetylation blocks cGAS activity and inhibits self-DNA-induced
RT autoimmunity.";
RL Cell 176:1447-1460(2019).
RN [40]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 225-GLU--ASP-227 AND 407-LYS--LYS-411.
RX PubMed=31299200; DOI=10.1016/j.cell.2019.05.035;
RA Zierhut C., Yamaguchi N., Paredes M., Luo J.D., Carroll T., Funabiki H.;
RT "The cytoplasmic DNA sensor cGAS promotes mitotic cell death.";
RL Cell 178:302-315(2019).
RN [41]
RP SUBCELLULAR LOCATION.
RX PubMed=30811988; DOI=10.1016/j.celrep.2019.01.105;
RA Gentili M., Lahaye X., Nadalin F., Nader G.P.F., Puig Lombardi E.,
RA Herve S., De Silva N.S., Rookhuizen D.C., Zueva E., Goudot C., Maurin M.,
RA Bochnakian A., Amigorena S., Piel M., Fachinetti D., Londono-Vallejo A.,
RA Manel N.;
RT "The N-Terminal domain of cGAS determines preferential association with
RT centromeric DNA and innate immune activation in the nucleus.";
RL Cell Rep. 26:2377-2393(2019).
RN [42]
RP SUBCELLULAR LOCATION, AND MUTAGENESIS OF ARG-236 AND ARG-255.
RX PubMed=31808743; DOI=10.7554/elife.47491;
RA Volkman H.E., Cambier S., Gray E.E., Stetson D.B.;
RT "Tight nuclear tethering of cGAS is essential for preventing
RT autoreactivity.";
RL Elife 8:0-0(2019).
RN [43]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-171; LYS-173;
RP 225-GLU--ASP-227; LYS-394 AND 396-CYS-CYS-397.
RX PubMed=31544964; DOI=10.15252/embj.2019102718;
RA Jiang H., Xue X., Panda S., Kawale A., Hooy R.M., Liang F., Sohn J.,
RA Sung P., Gekara N.O.;
RT "Chromatin-bound cGAS is an inhibitor of DNA repair and hence accelerates
RT genome destabilization and cell death.";
RL EMBO J. 38:e102718-e102718(2019).
RN [44]
RP UBIQUITINATION, AND DEUBIQUITINATION.
RX PubMed=31534008; DOI=10.4049/jimmunol.1900514;
RA Guo Y., Jiang F., Kong L., Li B., Yang Y., Zhang L., Liu B., Zheng Y.,
RA Gao C.;
RT "USP27X deubiquitinates and stabilizes the DNA sensor cGAS to regulate
RT cytosolic DNA-mediated signaling.";
RL J. Immunol. 203:2049-2054(2019).
RN [45]
RP PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF ASP-319.
RX PubMed=30878284; DOI=10.1016/j.molcel.2019.02.013;
RA Ning X., Wang Y., Jing M., Sha M., Lv M., Gao P., Zhang R., Huang X.,
RA Feng J.M., Jiang Z.;
RT "Apoptotic caspases suppress type i interferon production via the cleavage
RT of cGAS, MAVS, and IRF3.";
RL Mol. Cell 74:19-31(2019).
RN [46]
RP INTERACTION WITH HUMAN CYTOMEGALOVIRUS PROTEIN UL42 (MICROBIAL INFECTION).
RX PubMed=31107917; DOI=10.1371/journal.ppat.1007691;
RA Fu Y.Z., Guo Y., Zou H.M., Su S., Wang S.Y., Yang Q., Luo M.H., Wang Y.Y.;
RT "Human cytomegalovirus protein UL42 antagonizes cGAS/MITA-mediated innate
RT antiviral response.";
RL PLoS Pathog. 15:e1007691-e1007691(2019).
RN [47]
RP FUNCTION.
RX PubMed=33031745; DOI=10.1016/j.cell.2020.09.020;
RA Yu C.H., Davidson S., Harapas C.R., Hilton J.B., Mlodzianoski M.J.,
RA Laohamonthonkul P., Louis C., Low R.R.J., Moecking J., De Nardo D.,
RA Balka K.R., Calleja D.J., Moghaddas F., Ni E., McLean C.A., Samson A.L.,
RA Tyebji S., Tonkin C.J., Bye C.R., Turner B.J., Pepin G., Gantier M.P.,
RA Rogers K.L., McArthur K., Crouch P.J., Masters S.L.;
RT "TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING
RT in ALS.";
RL Cell 183:636-649(2020).
RN [48]
RP FUNCTION, CATALYTIC ACTIVITY, AND COFACTOR.
RX PubMed=32814054; DOI=10.1016/j.celrep.2020.108053;
RA Zhao Z., Ma Z., Wang B., Guan Y., Su X.D., Jiang Z.;
RT "Mn2+ directly activates cGAS and structural analysis suggests Mn2+ Induces
RT a noncanonical catalytic synthesis of 2'3'-cGAMP.";
RL Cell Rep. 32:108053-108053(2020).
RN [49]
RP SUBCELLULAR LOCATION, PHOSPHORYLATION AT SER-305, AND MUTAGENESIS OF
RP SER-305.
RX PubMed=32351706; DOI=10.1038/s41421-020-0162-2;
RA Zhong L., Hu M.M., Bian L.J., Liu Y., Chen Q., Shu H.B.;
RT "Phosphorylation of cGAS by CDK1 impairs self-DNA sensing in mitosis.";
RL Cell Discov. 6:26-26(2020).
RN [50]
RP FUNCTION.
RX PubMed=32852081; DOI=10.15252/embj.2019103958;
RA Sumner R.P., Harrison L., Touizer E., Peacock T.P., Spencer M.,
RA Zuliani-Alvarez L., Towers G.J.;
RT "Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA.";
RL EMBO J. 39:e103958-e103958(2020).
RN [51]
RP INTERACTION WITH TRIM14.
RX PubMed=32404352; DOI=10.4049/jimmunol.1901511;
RA Hoffpauir C.T., Bell S.L., West K.O., Jing T., Wagner A.R., Torres-Odio S.,
RA Cox J.S., West A.P., Li P., Patrick K.L., Watson R.O.;
RT "TRIM14 Is a Key Regulator of the Type I IFN Response during Mycobacterium
RT tuberculosis Infection.";
RL J. Immunol. 205:153-167(2020).
RN [52]
RP INTERACTION WITH NUCLEOSOMES, AND MUTAGENESIS OF ARG-236; ARG-246; LYS-252;
RP LYS-254; ARG-255; LYS-258; LYS-327; LYS-347; ARG-349; LYS-350 AND LYS-355.
RX PubMed=32911481; DOI=10.1038/s41586-020-2749-z;
RA Zhao B., Xu P., Rowlett C.M., Jing T., Shinde O., Lei Y., West A.P.,
RA Liu W.R., Li P.;
RT "The molecular basis of tight nuclear tethering and inactivation of cGAS.";
RL Nature 587:673-677(2020).
RN [53]
RP INTERACTION WITH NUCLEOSOMES, AND MUTAGENESIS OF LYS-236 AND ARG-255.
RX PubMed=32911480; DOI=10.1038/s41586-020-2748-0;
RA Michalski S., de Oliveira Mann C.C., Stafford C.A., Witte G., Bartho J.,
RA Lammens K., Hornung V., Hopfner K.P.;
RT "Structural basis for sequestration and autoinhibition of cGAS by
RT chromatin.";
RL Nature 587:678-682(2020).
RN [54]
RP FUNCTION, SUBUNIT, PHOSPHORYLATION AT THR-68 AND SER-213, ACTIVITY
RP REGULATION, AND MUTAGENESIS OF THR-68 AND SER-213.
RX PubMed=33273464; DOI=10.1038/s41467-020-19941-0;
RA Sun X., Liu T., Zhao J., Xia H., Xie J., Guo Y., Zhong L., Li M., Yang Q.,
RA Peng C., Rouvet I., Belot A., Shu H.B., Feng P., Zhang J.;
RT "DNA-PK deficiency potentiates cGAS-mediated antiviral innate immunity.";
RL Nat. Commun. 11:6182-6182(2020).
RN [55]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=33230297; DOI=10.1038/s41588-020-00737-3;
RA Uggenti C., Lepelley A., Depp M., Badrock A.P., Rodero M.P., El-Daher M.T.,
RA Rice G.I., Dhir S., Wheeler A.P., Dhir A., Albawardi W., Fremond M.L.,
RA Seabra L., Doig J., Blair N., Martin-Niclos M.J., Della Mina E.,
RA Rubio-Roldan A., Garcia-Perez J.L., Sproul D., Rehwinkel J., Hertzog J.,
RA Boland-Auge A., Olaso R., Deleuze J.F., Baruteau J., Brochard K.,
RA Buckley J., Cavallera V., Cereda C., De Waele L.M.H., Dobbie A.,
RA Doummar D., Elmslie F., Koch-Hogrebe M., Kumar R., Lamb K.,
RA Livingston J.H., Majumdar A., Lorenco C.M., Orcesi S., Peudenier S.,
RA Rostasy K., Salmon C.A., Scott C., Tonduti D., Touati G., Valente M.,
RA van der Linden H. Jr., Van Esch H., Vermelle M., Webb K., Jackson A.P.,
RA Reijns M.A.M., Gilbert N., Crow Y.J.;
RT "cGAS-mediated induction of type I interferon due to inborn errors of
RT histone pre-mRNA processing.";
RL Nat. Genet. 52:1364-1372(2020).
RN [56]
RP FUNCTION, ACTIVITY REGULATION, ACETYLATION AT LYS-21; LYS-47; LYS-50;
RP LYS-56; LYS-62; LYS-63; LYS-82 AND LYS-83, AND MUTAGENESIS OF LYS-47;
RP LYS-56; LYS-62 AND LYS-83.
RX PubMed=32817552; DOI=10.1073/pnas.1922330117;
RA Song Z.M., Lin H., Yi X.M., Guo W., Hu M.M., Shu H.B.;
RT "KAT5 acetylates cGAS to promote innate immune response to DNA virus.";
RL Proc. Natl. Acad. Sci. U.S.A. 117:21568-21575(2020).
RN [57]
RP PHOSPHORYLATION AT THR-91; SER-98; SER-434 AND SER-435, DEPHOSPHORYLATION,
RP ACTIVITY REGULATION, AND MUTAGENESIS OF SER-435.
RX PubMed=32474700; DOI=10.1007/s13238-020-00729-3;
RA Li M., Shu H.B.;
RT "Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity
RT and innate antiviral response.";
RL Protein Cell 11:584-599(2020).
RN [58]
RP SUBCELLULAR LOCATION, AND ACTIVITY REGULATION.
RX PubMed=32792394; DOI=10.1126/science.aaw6421;
RA Guey B., Wischnewski M., Decout A., Makasheva K., Kaynak M., Sakar M.S.,
RA Fierz B., Ablasser A.;
RT "BAF restricts cGAS on nuclear DNA to prevent innate immune activation.";
RL Science 369:823-828(2020).
RN [59]
RP FUNCTION, NUCLEAR EXPORT SIGNAL MOTIF, AND MUTAGENESIS OF 169-LEU--LEU-174
RP AND LEU-172.
RX PubMed=33406424; DOI=10.1016/j.celrep.2020.108586;
RA Sun H., Huang Y., Mei S., Xu F., Liu X., Zhao F., Yin L., Zhang D., Wei L.,
RA Wu C., Ma S., Wang J., Cen S., Liang C., Hu S., Guo F.;
RT "A Nuclear export signal is required for cGAS to sense cytosolic DNA.";
RL Cell Rep. 34:108586-108586(2021).
RN [60]
RP ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=33476576; DOI=10.1016/j.molcel.2020.12.037;
RA Mohr L., Toufektchan E., von Morgen P., Chu K., Kapoor A., Maciejowski J.;
RT "ER-directed TREX1 limits cGAS activation at micronuclei.";
RL Mol. Cell 81:724-738(2021).
RN [61]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=33606975; DOI=10.1016/j.molcel.2021.01.024;
RA Zhou W., Mohr L., Maciejowski J., Kranzusch P.J.;
RT "cGAS phase separation inhibits TREX1-mediated DNA degradation and enhances
RT cytosolic DNA sensing.";
RL Mol. Cell 81:739-755(2021).
RN [62]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP LYS-347; ARG-349; LYS-350 AND ARG-353.
RX PubMed=34111399; DOI=10.1016/j.molcel.2021.05.018;
RA Wan L., Juszkiewicz S., Blears D., Bajpe P.K., Han Z., Faull P., Mitter R.,
RA Stewart A., Snijders A.P., Hegde R.S., Svejstrup J.Q.;
RT "Translation stress and collided ribosomes are co-activators of cGAS.";
RL Mol. Cell 81:2808-2822(2021).
RN [63]
RP ACTIVITY REGULATION (MICROBIAL INFECTION), INTERACTION WITH HHV-8 PROTEIN
RP ORF52 (MICROBIAL INFECTION), INTERACTION WITH HERPES SIMPLEX VIRUS 1
RP PROTEIN UL49/VP22 (MICROBIAL INFECTION), AND INTERACTION WITH HERPESVIRUS 3
RP PROTEIN ORF9 (MICROBIAL INFECTION).
RX PubMed=34015248; DOI=10.1016/j.molcel.2021.05.002;
RA Xu G., Liu C., Zhou S., Li Q., Feng Y., Sun P., Feng H., Gao Y., Zhu J.,
RA Luo X., Zhan Q., Liu S., Zhu S., Deng H., Li D., Gao P.;
RT "Viral tegument proteins restrict cGAS-DNA phase separation to mediate
RT immune evasion.";
RL Mol. Cell 81:2823-2837(2021).
RN [64]
RP DEGRADATION BY CHIKUNGUNYA VIRUS CAPSID PROTEIN (MICROBIAL INFECTION).
RX PubMed=33057424; DOI=10.1371/journal.ppat.1008999;
RA Webb L.G., Veloz J., Pintado-Silva J., Zhu T., Rangel M.V., Mutetwa T.,
RA Zhang L., Bernal-Rubio D., Figueroa D., Carrau L., Fenutria R., Potla U.,
RA Reid S.P., Yount J.S., Stapleford K.A., Aguirre S., Fernandez-Sesma A.;
RT "Chikungunya virus antagonizes cGAS-STING mediated type-I interferon
RT responses by degrading cGAS.";
RL PLoS Pathog. 16:e1008999-e1008999(2020).
RN [65]
RP ACTIVITY REGULATION (MICROBIAL INFECTION), AND INTERACTION WITH HHV-8
RP PROTEIN ORF52 (MICROBIAL INFECTION).
RX PubMed=34387695; DOI=10.1093/nar/gkab689;
RA Bhowmik D., Du M., Tian Y., Ma S., Wu J., Chen Z., Yin Q., Zhu F.;
RT "Cooperative DNA binding mediated by KicGAS/ORF52 oligomerization allows
RT inhibition of DNA-induced phase separation and activation of cGAS.";
RL Nucleic Acids Res. 49:9389-9403(2021).
RN [66]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, DOMAIN, PHOSPHORYLATION
RP AT SER-13; SER-37; SER-64; THR-68; THR-91; SER-116; SER-129; SER-143 AND
RP SER-305, AND MUTAGENESIS OF SER-13; THR-18; SER-23; THR-35; SER-37; SER-57;
RP SER-59; SER-64; THR-68; THR-77; THR-91; SER-94; THR-97; SER-98; SER-116;
RP SER-120; SER-129; THR-130; SER-143 AND SER-149.
RX PubMed=33542149; DOI=10.1126/science.abc5386;
RA Li T., Huang T., Du M., Chen X., Du F., Ren J., Chen Z.J.;
RT "Phosphorylation and chromatin tethering prevent cGAS activation during
RT mitosis.";
RL Science 371:0-0(2021).
RN [67]
RP FUNCTION.
RX PubMed=33688080; DOI=10.1126/scisignal.aax7942;
RA Apel F., Andreeva L., Knackstedt L.S., Streeck R., Frese C.K., Goosmann C.,
RA Hopfner K.P., Zychlinsky A.;
RT "The cytosolic DNA sensor cGAS recognizes neutrophil extracellular traps.";
RL Sci. Signal. 14:0-0(2021).
RN [68]
RP FUNCTION.
RX PubMed=35045565; DOI=10.1038/s41586-022-04421-w;
RA Di Domizio J., Gulen M.F., Saidoune F., Thacker V.V., Yatim A., Sharma K.,
RA Nass T., Guenova E., Schaller M., Conrad C., Goepfert C., De Leval L.,
RA von Garnier C., Berezowska S., Dubois A., Gilliet M., Ablasser A.;
RT "The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.";
RL Nature 603:145-151(2022).
RN [69]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 157-222 IN COMPLEX WITH ZINC IONS,
RP FUNCTION, CATALYTIC ACTIVITY, DOMAIN, ACTIVITY REGULATION, DNA-BINDING, AND
RP MUTAGENESIS OF LYS-171; LYS-173; 225-GLU--ASP-227; LYS-384; HIS-390;
RP LYS-394; CYS-396; CYS-397; CYS-404; LYS-407 AND LYS-414.
RX PubMed=23707061; DOI=10.1016/j.celrep.2013.05.008;
RA Kranzusch P.J., Lee A.S., Berger J.M., Doudna J.A.;
RT "Structure of human cGAS reveals a conserved family of second-messenger
RT enzymes in innate immunity.";
RL Cell Rep. 3:1362-1368(2013).
RN [70]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 157-522 IN COMPLEX WITH ZINC.
RX PubMed=24332030; DOI=10.1016/j.immuni.2013.10.019;
RA Li X., Shu C., Yi G., Chaton C.T., Shelton C.L., Diao J., Zuo X., Kao C.C.,
RA Herr A.B., Li P.;
RT "Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced
RT oligomerization.";
RL Immunity 39:1019-1031(2013).
RN [71]
RP X-RAY CRYSTALLOGRAPHY (1.95 ANGSTROMS) OF 161-522 IN COMPLEX WITH ZINC,
RP FUNCTION, DNA-BINDING, AND MUTAGENESIS OF LYS-384; LYS-400; LYS-403;
RP LYS-407 AND LYS-411.
RX PubMed=24116191; DOI=10.1371/journal.pone.0076983;
RA Kato K., Ishii R., Goto E., Ishitani R., Tokunaga F., Nureki O.;
RT "Structural and functional analyses of DNA-sensing and immune activation by
RT human cGAS.";
RL PLoS ONE 8:E76983-E76983(2013).
RN [72]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 161-522 IN COMPLEX WITH ZINC AND
RP 2',3'-CGAMP, FUNCTION, AND MUTAGENESIS OF ARG-236; LYS-254; LYS-327;
RP LYS-347; ARG-353 AND LYS-394.
RX PubMed=24462292; DOI=10.1016/j.celrep.2014.01.003;
RA Zhang X., Wu J., Du F., Xu H., Sun L., Chen Z., Brautigam C.A., Zhang X.,
RA Chen Z.J.;
RT "The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and
RT undergoes switch-like conformational changes in the activation loop.";
RL Cell Rep. 6:421-430(2014).
RN [73] {ECO:0007744|PDB:5V8O, ECO:0007744|PDB:6NAO, ECO:0007744|PDB:6NFG, ECO:0007744|PDB:6NFO}
RP X-RAY CRYSTALLOGRAPHY (2.76 ANGSTROMS) OF 161-522 IN COMPLEX WITH ZINC AND
RP INHIBITOR PF-06928215, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND
RP BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=28934246; DOI=10.1371/journal.pone.0184843;
RA Hall J., Brault A., Vincent F., Weng S., Wang H., Dumlao D., Aulabaugh A.,
RA Aivazian D., Castro D., Chen M., Culp J., Dower K., Gardner J.,
RA Hawrylik S., Golenbock D., Hepworth D., Horn M., Jones L., Jones P.,
RA Latz E., Li J., Lin L.L., Lin W., Lin D., Lovering F., Niljanskul N.,
RA Nistler R., Pierce B., Plotnikova O., Schmitt D., Shanker S., Smith J.,
RA Snyder W., Subashi T., Trujillo J., Tyminski E., Wang G., Wong J.,
RA Lefker B., Dakin L., Leach K.;
RT "Discovery of PF-06928215 as a high affinity inhibitor of cGAS enabled by a
RT novel fluorescence polarization assay.";
RL PLoS ONE 12:E0184843-E0184843(2017).
RN [74] {ECO:0007744|PDB:5VDO, ECO:0007744|PDB:5VDP, ECO:0007744|PDB:5VDQ, ECO:0007744|PDB:5VDR, ECO:0007744|PDB:5VDS, ECO:0007744|PDB:5VDT, ECO:0007744|PDB:5VDU, ECO:0007744|PDB:5VDV, ECO:0007744|PDB:5VDW}
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 161-522 IN COMPLEX WITH ZINC.
RX PubMed=28940468; DOI=10.1002/pro.3304;
RA Hall J., Ralph E.C., Shanker S., Wang H., Byrnes L.J., Horst R., Wong J.,
RA Brault A., Dumlao D., Smith J.F., Dakin L.A., Schmitt D.C., Trujillo J.,
RA Vincent F., Griffor M., Aulabaugh A.E.;
RT "The catalytic mechanism of cyclic GMP-AMP synthase (cGAS) and implications
RT for innate immunity and inhibition.";
RL Protein Sci. 26:2367-2380(2017).
RN [75] {ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA}
RP X-RAY CRYSTALLOGRAPHY (2.26 ANGSTROMS) OF 157-522 IN COMPLEX WITH ZINC;
RP MAGNESIUM; DNA AND ATP, FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION,
RP AND MUTAGENESIS OF LYS-187; LEU-195; SER-434 AND ASN-482.
RX PubMed=30007416; DOI=10.1016/j.cell.2018.06.026;
RA Zhou W., Whiteley A.T., de Oliveira Mann C.C., Morehouse B.R., Nowak R.P.,
RA Fischer E.S., Gray N.S., Mekalanos J.J., Kranzusch P.J.;
RT "Structure of the human cGAS-DNA complex reveals enhanced control of immune
RT surveillance.";
RL Cell 174:300-311(2018).
RN [76] {ECO:0007744|PDB:6MJU, ECO:0007744|PDB:6MJW, ECO:0007744|PDB:6MJX}
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 152-522 IN COMPLEX WITH SMALL
RP INHIBITORS; 2',3'-CGAMP AND ZINC, COFACTOR, AND ACTIVITY REGULATION.
RX PubMed=31113940; DOI=10.1038/s41467-019-08620-4;
RA Lama L., Adura C., Xie W., Tomita D., Kamei T., Kuryavyi V., Gogakos T.,
RA Steinberg J.I., Miller M., Ramos-Espiritu L., Asano Y., Hashizume S.,
RA Aida J., Imaeda T., Okamoto R., Jennings A.J., Michino M., Kuroita T.,
RA Stamford A., Gao P., Meinke P., Glickman J.F., Patel D.J., Tuschl T.;
RT "Development of human cGAS-specific small-molecule inhibitors for
RT repression of dsDNA-triggered interferon expression.";
RL Nat. Commun. 10:2261-2261(2019).
RN [77] {ECO:0007744|PDB:6EDB, ECO:0007744|PDB:6EDC, ECO:0007744|PDB:6O47}
RP X-RAY CRYSTALLOGRAPHY (2.20 ANGSTROMS) OF 152-522 IN COMPLEX WITH DNA AND
RP ZINC, FUNCTION, CATALYTIC ACTIVITY, DNA-BINDING, COFACTOR, SUBUNIT,
RP MUTAGENESIS OF LYS-275; 279-LYS--LYS-282; LYS-279; LYS-285;
RP 300-ARG-LYS-301; ARG-300 AND 427-LYS-LYS-428, CHARACTERIZATION OF VARIANT
RP THR-432, AND VARIANT GLU-303.
RX PubMed=31142647; DOI=10.1073/pnas.1905013116;
RA Xie W., Lama L., Adura C., Tomita D., Glickman J.F., Tuschl T., Patel D.J.;
RT "Human cGAS catalytic domain has an additional DNA-binding interface that
RT enhances enzymatic activity and liquid-phase condensation.";
RL Proc. Natl. Acad. Sci. U.S.A. 116:11946-11955(2019).
RN [78] {ECO:0007744|PDB:7CCQ, ECO:0007744|PDB:7CCR}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.80 ANGSTROMS) OF 157-522 IN COMPLEX
RP WITH NUCLEOSOME CORE, FUNCTION, INTERACTION WITH NUCLEOSOMES, ACTIVITY
RP REGULATION, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF ARG-236;
RP LYS-254; ARG-255; LYS-258; LYS-327; SER-328; SER-329; ARG-349; LYS-350 AND
RP ARG-353.
RX PubMed=33051594; DOI=10.1038/s41422-020-00422-4;
RA Cao D., Han X., Fan X., Xu R.M., Zhang X.;
RT "Structural basis for nucleosome-mediated inhibition of cGAS activity.";
RL Cell Res. 30:1088-1097(2020).
RN [79] {ECO:0007744|PDB:6LRC, ECO:0007744|PDB:6LRE, ECO:0007744|PDB:6LRI, ECO:0007744|PDB:6LRJ, ECO:0007744|PDB:6LRK, ECO:0007744|PDB:6LRL}
RP X-RAY CRYSTALLOGRAPHY (1.83 ANGSTROMS) OF 157-522 IN COMPLEX WITH ZINC;
RP INHIBITOR PF-06928215 AND OTHER INHIBITORS, COFACTOR, AND ACTIVITY
RP REGULATION.
RX PubMed=32459092; DOI=10.1021/acs.jcim.0c00171;
RA Zhao W., Xiong M., Yuan X., Li M., Sun H., Xu Y.;
RT "In silico screening-based discovery of novel inhibitors of human cyclic
RT GMP-AMP synthase: a cross-validation study of molecular docking and
RT experimental testing.";
RL J. Chem. Inf. Model. 60:3265-3276(2020).
RN [80] {ECO:0007744|PDB:6Y5D, ECO:0007744|PDB:6Y5E}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.15 ANGSTROMS) OF 161-522 IN COMPLEX
RP WITH NUCLEOSOME CORE AND ZINC, FUNCTION, COFACTOR, INTERACTION WITH
RP NUCLEOSOMES, ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF ARG-236;
RP ARG-255 AND LYS-394.
RX PubMed=32911482; DOI=10.1038/s41586-020-2750-6;
RA Pathare G.R., Decout A., Glueck S., Cavadini S., Makasheva K., Hovius R.,
RA Kempf G., Weiss J., Kozicka Z., Guey B., Melenec P., Fierz B., Thomae N.H.,
RA Ablasser A.;
RT "Structural mechanism of cGAS inhibition by the nucleosome.";
RL Nature 587:668-672(2020).
RN [81] {ECO:0007744|PDB:7C0M}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.90 ANGSTROMS) OF 151-522 IN COMPLEX
RP WITH NUCLEOSOME CORE AND ZINC, FUNCTION, COFACTOR, INTERACTION WITH
RP NUCLEOSOMES, ACTIVITY REGULATION, DOMAIN, AND MUTAGENESIS OF ARG-255.
RX PubMed=32912999; DOI=10.1126/science.abd0237;
RA Kujirai T., Zierhut C., Takizawa Y., Kim R., Negishi L., Uruma N.,
RA Hirai S., Funabiki H., Kurumizaka H.;
RT "Structural basis for the inhibition of cGAS by nucleosomes.";
RL Science 370:455-458(2020).
CC -!- FUNCTION: Nucleotidyltransferase that catalyzes the formation of cyclic
CC GMP-AMP (2',3'-cGAMP) from ATP and GTP and plays a key role in innate
CC immunity (PubMed:23258413, PubMed:24077100, PubMed:25131990,
CC PubMed:23707061, PubMed:23722159, PubMed:29976794, PubMed:30799039,
CC PubMed:21478870, PubMed:23707065, PubMed:24116191, PubMed:24462292,
CC PubMed:32814054, PubMed:33273464, PubMed:26300263, PubMed:33542149,
CC PubMed:31142647). Catalysis involves both the formation of a 2',5'
CC phosphodiester linkage at the GpA step and the formation of a 3',5'
CC phosphodiester linkage at the ApG step, producing c[G(2',5')pA(3',5')p]
CC (PubMed:28214358, PubMed:28363908). Acts as a key DNA sensor: directly
CC binds double-stranded DNA (dsDNA), inducing the formation of liquid-
CC like droplets in which CGAS is activated, leading to synthesis of
CC 2',3'-cGAMP, a second messenger that binds to and activates STING1,
CC thereby triggering type-I interferon production (PubMed:28314590,
CC PubMed:28363908, PubMed:29976794, PubMed:33230297, PubMed:32817552,
CC PubMed:33606975). Preferentially recognizes and binds curved long
CC dsDNAs of a minimal length of 40 bp (PubMed:30007416). Acts as a key
CC foreign DNA sensor, the presence of double-stranded DNA (dsDNA) in the
CC cytoplasm being a danger signal that triggers the immune responses
CC (PubMed:28363908). Has antiviral activity by sensing the presence of
CC dsDNA from DNA viruses in the cytoplasm (PubMed:28363908). Also acts as
CC an innate immune sensor of infection by retroviruses, such as HIV-2, by
CC detecting the presence of reverse-transcribed DNA in the cytosol
CC (PubMed:23929945, PubMed:24269171, PubMed:30270045, PubMed:32852081).
CC In contrast, HIV-1 is poorly sensed by CGAS, due to its capsid that
CC cloaks viral DNA from CGAS detection (PubMed:24269171, PubMed:30270045,
CC PubMed:32852081). Detection of retroviral reverse-transcribed DNA in
CC the cytosol may be indirect and be mediated via interaction with PQBP1,
CC which directly binds reverse-transcribed retroviral DNA
CC (PubMed:26046437). Also detects the presence of DNA from bacteria, such
CC as M.tuberculosis (PubMed:26048138). 2',3'-cGAMP can be transferred
CC from producing cells to neighboring cells through gap junctions,
CC leading to promote STING1 activation and convey immune response to
CC connecting cells (PubMed:24077100). 2',3'-cGAMP can also be transferred
CC between cells by virtue of packaging within viral particles
CC contributing to IFN-induction in newly infected cells in a cGAS-
CC independent but STING1-dependent manner (PubMed:26229115). Also senses
CC the presence of neutrophil extracellular traps (NETs) that are
CC translocated to the cytosol following phagocytosis, leading to
CC synthesis of 2',3'-cGAMP (PubMed:33688080). In addition to foreign DNA,
CC can also be activated by endogenous nuclear or mitochondrial DNA
CC (PubMed:31299200, PubMed:28738408, PubMed:28759889, PubMed:33230297,
CC PubMed:33031745). When self-DNA leaks into the cytosol during cellular
CC stress (such as mitochondrial stress, SARS-CoV-2 infection causing
CC severe COVID-19 disease, DNA damage, mitotic arrest or senescence), or
CC is present in form of cytosolic micronuclei, CGAS is activated leading
CC to a state of sterile inflammation (PubMed:31299200, PubMed:28738408,
CC PubMed:28759889, PubMed:33230297, PubMed:33031745, PubMed:35045565).
CC Acts as a regulator of cellular senescence by binding to cytosolic
CC chromatin fragments that are present in senescent cells, leading to
CC trigger type-I interferon production via STING1 and promote cellular
CC senescence (By similarity). Also involved in the inflammatory response
CC to genome instability and double-stranded DNA breaks: acts by
CC localizing to micronuclei arising from genome instability
CC (PubMed:28738408, PubMed:28759889). Micronuclei, which are frequently
CC found in cancer cells, consist of chromatin surrounded by their own
CC nuclear membrane: following breakdown of the micronuclear envelope, a
CC process associated with chromothripsis, CGAS binds self-DNA exposed to
CC the cytosol, leading to 2',3'-cGAMP synthesis and subsequent activation
CC of STING1 and type-I interferon production (PubMed:28738408,
CC PubMed:28759889). Activated in response to prolonged mitotic arrest,
CC promoting mitotic cell death (PubMed:31299200). In a healthy cell, CGAS
CC is however kept inactive even in cellular events that directly expose
CC it to self-DNA, such as mitosis, when cGAS associates with chromatin
CC directly after nuclear envelope breakdown or remains in the form of
CC postmitotic persistent nuclear cGAS pools bound to chromatin
CC (PubMed:31299200, PubMed:33542149). Nuclear CGAS is inactivated by
CC chromatin via direct interaction with nucleosomes, which block CGAS
CC from DNA binding and thus prevent CGAS-induced autoimmunity
CC (PubMed:31299200, PubMed:33542149, PubMed:33051594, PubMed:32911482,
CC PubMed:32912999). Also acts as a suppressor of DNA repair in response
CC to DNA damage: inhibits homologous recombination repair by interacting
CC with PARP1, the CGAS-PARP1 interaction leading to impede the formation
CC of the PARP1-TIMELESS complex (PubMed:30356214, PubMed:31544964). In
CC addition to DNA, also sense translation stress: in response to
CC translation stress, translocates to the cytosol and associates with
CC collided ribosomes, promoting its activation and triggering type-I
CC interferon production (PubMed:34111399). In contrast to other mammals,
CC human CGAS displays species-specific mechanisms of DNA recognition and
CC produces less 2',3'-cGAMP, allowing a more fine-tuned response to
CC pathogens (PubMed:30007416). {ECO:0000250|UniProtKB:Q8C6L5,
CC ECO:0000269|PubMed:21478870, ECO:0000269|PubMed:23258413,
CC ECO:0000269|PubMed:23707061, ECO:0000269|PubMed:23707065,
CC ECO:0000269|PubMed:23722159, ECO:0000269|PubMed:23929945,
CC ECO:0000269|PubMed:24077100, ECO:0000269|PubMed:24116191,
CC ECO:0000269|PubMed:24269171, ECO:0000269|PubMed:24462292,
CC ECO:0000269|PubMed:25131990, ECO:0000269|PubMed:26046437,
CC ECO:0000269|PubMed:26048138, ECO:0000269|PubMed:26229115,
CC ECO:0000269|PubMed:26300263, ECO:0000269|PubMed:28214358,
CC ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:28363908,
CC ECO:0000269|PubMed:28738408, ECO:0000269|PubMed:28759889,
CC ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416,
CC ECO:0000269|PubMed:30270045, ECO:0000269|PubMed:30356214,
CC ECO:0000269|PubMed:30799039, ECO:0000269|PubMed:31142647,
CC ECO:0000269|PubMed:31299200, ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:32817552,
CC ECO:0000269|PubMed:32852081, ECO:0000269|PubMed:32911482,
CC ECO:0000269|PubMed:32912999, ECO:0000269|PubMed:33031745,
CC ECO:0000269|PubMed:33051594, ECO:0000269|PubMed:33230297,
CC ECO:0000269|PubMed:33273464, ECO:0000269|PubMed:33542149,
CC ECO:0000269|PubMed:33606975, ECO:0000269|PubMed:33688080,
CC ECO:0000269|PubMed:34111399, ECO:0000269|PubMed:35045565}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + GTP = 2',3'-cGAMP + 2 diphosphate; Xref=Rhea:RHEA:42064,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:37565,
CC ChEBI:CHEBI:143093; EC=2.7.7.86;
CC Evidence={ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:23707061,
CC ECO:0000269|PubMed:23722159, ECO:0000269|PubMed:25131990,
CC ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:29976794,
CC ECO:0000269|PubMed:30799039, ECO:0000269|PubMed:31142647,
CC ECO:0000269|PubMed:32814054, ECO:0000269|PubMed:33542149};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:42065;
CC Evidence={ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:28934246};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:30007416};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000269|PubMed:32814054};
CC Note=Binds 1 Mg(2+) ion per subunit (PubMed:30007416). Is also active
CC with Mn(2+) (PubMed:32814054). Mn(2+)-activated enyzme forms an
CC inverted pppGp(2'-5')A intermediate, suggesting a non-canonical but
CC accelerated 2',3'-cGAMP cyclization without substrate flip-over (By
CC similarity). Mn(2+) ions are coordinated by triphosphate moiety of the
CC inverted substrate, independent of the catalytic triad residues (By
CC similarity). {ECO:0000250|UniProtKB:Q8C6L5,
CC ECO:0000269|PubMed:30007416, ECO:0000269|PubMed:32814054};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:31113940,
CC ECO:0000269|PubMed:31142647, ECO:0000269|PubMed:32459092,
CC ECO:0000269|PubMed:32911482, ECO:0000269|PubMed:32912999};
CC Note=Undergoes a liquid-like phase transition after binding to DNA,
CC which is dependent on zinc. {ECO:0000269|PubMed:29976794};
CC -!- ACTIVITY REGULATION: The enzyme activity is strongly increased by
CC double-stranded DNA (dsDNA), but not by single-stranded DNA or RNA
CC (PubMed:23258413, PubMed:23707061, PubMed:26300263). DNA-binding
CC induces the formation of liquid-like droplets in which CGAS is
CC activated (PubMed:29976794, PubMed:33606975). Liquid-like droplets also
CC create a selective environment that restricts entry of negative
CC regulators, such as TREX1 or BANF1/BAF, allowing sensing of DNA
CC (PubMed:33606975). A number of mechanisms exist to restrict its
CC activity toward self-DNA (PubMed:31299200, PubMed:33051594,
CC PubMed:32911482, PubMed:32912999, PubMed:33542149, PubMed:32792394).
CC The nucleotidyltransferase activity is inhibited in the nucleus via its
CC association with nucleosomes: interacts with the acidic patch of
CC histones H2A and H2B, thereby blocking DNA-binding and subsequent
CC activation (PubMed:31299200, PubMed:33051594, PubMed:32911482,
CC PubMed:32912999). CGAS is also inactive when associated with mitotic
CC chromatin (PubMed:33542149). Chromatin-bound CGAS cannot be activated
CC by exogenous DNA in mitotic cells: phosphorylation of the N-terminal
CC disordered part by AURKB during the G2-M transition blocks CGAS liquid
CC phase separation and activation (PubMed:33542149). Activity toward
CC self-DNA is inhibited by BANF1/BAF upon acute loss of nuclear membrane
CC integrity: BANF1/BAF acts by outcompeting CGAS for DNA-binding, thereby
CC preventing CGAS activation (PubMed:32792394). DNA-induced activation at
CC micronuclei is also limited by TREX1, which degrades micronuclear DNA
CC upon nuclear envelope rupture, thereby preventing CGAS activation
CC (PubMed:33476576). Acetylation at Lys-384, Lys-394 and Lys-414 inhibits
CC the cyclic GMP-AMP synthase activity (PubMed:30799039). Inhibited by
CC aspirin (acetylsalicylate) drug, which acetylates CGAS
CC (PubMed:30799039). Acetylation by KAT5 increases the cyclic GMP-AMP
CC synthase activity by promoting DNA-binding and subsequent activation
CC (PubMed:32817552). Phosphorylation at Ser-305 suppresses the
CC nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at
CC Ser-435 promotes the cyclic GMP-AMP synthase activity
CC (PubMed:32474700). Phosphorylation at Thr-68 and Ser-213 inhibits its
CC cyclic GMP-AMP synthase activity (PubMed:33273464). Ubiquitination at
CC Lys-173 and Lys-384 via 'Lys-27'-linked polyubiquitination enhances the
CC cyclic GMP-AMP synthase activity (PubMed:28273161). Monoubiquitination
CC at Lys-347 promotes oligomerization and subsequent activation
CC (PubMed:29426904). Sumoylation at Lys-347, Lys-384 and Lys-394 prevents
CC DNA-binding, oligomerization and nucleotidyltransferase activity (By
CC similarity). The enzyme activity is impaired by the cleavage at Asp-140
CC and Asp-157 produced by CASP1 (PubMed:28314590). In addition to DNA,
CC also activated by collided ribosomes upon translation stress:
CC specifically binds collided ribosomes, promoting its activation and
CC triggering type-I interferon production (PubMed:34111399). Strongly
CC inhibited by compound PF-06928215, which is specific for human protein
CC (PubMed:28934246, PubMed:30007416, PubMed:32459092). Inhibited by
CC small-molecule inhibitors with a pyridoindole tricyclic core G108, G140
CC and G150 (PubMed:31113940). {ECO:0000250|UniProtKB:Q8C6L5,
CC ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:23707061,
CC ECO:0000269|PubMed:26300263, ECO:0000269|PubMed:26440888,
CC ECO:0000269|PubMed:28273161, ECO:0000269|PubMed:28314590,
CC ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:29426904,
CC ECO:0000269|PubMed:29976794, ECO:0000269|PubMed:30007416,
CC ECO:0000269|PubMed:30799039, ECO:0000269|PubMed:31113940,
CC ECO:0000269|PubMed:31299200, ECO:0000269|PubMed:32459092,
CC ECO:0000269|PubMed:32474700, ECO:0000269|PubMed:32792394,
CC ECO:0000269|PubMed:32817552, ECO:0000269|PubMed:32911482,
CC ECO:0000269|PubMed:32912999, ECO:0000269|PubMed:33051594,
CC ECO:0000269|PubMed:33273464, ECO:0000269|PubMed:33476576,
CC ECO:0000269|PubMed:33542149, ECO:0000269|PubMed:33606975,
CC ECO:0000269|PubMed:34111399}.
CC -!- ACTIVITY REGULATION: (Microbial infection) Nucleotidyltransferase
CC activity is inhibited by different herpesvirus tegument proteins
CC (Herpes simplex virus 1 tegument protein VP22, herpes virus 8 protein
CC ORF52 and herpesvirus 3 tegument protein VP22/ORF9) (PubMed:34015248,
CC PubMed:34387695). Viral tegument proteins act by disrupting liquid-like
CC droplets in which CGAS is activated, thereby preventing CGAS activity
CC (PubMed:34015248, PubMed:34387695). {ECO:0000269|PubMed:34015248,
CC ECO:0000269|PubMed:34387695}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=35 uM for ATP (with 1 mM GTP) {ECO:0000269|PubMed:28934246};
CC KM=30 uM for GTP (with 1 mM ATP) {ECO:0000269|PubMed:28934246};
CC -!- SUBUNIT: Monomer in the absence of DNA (PubMed:28363908). Homodimer in
CC presence of dsDNA: forms a 2:2 dimer with two enzymes binding to two
CC DNA molecules (PubMed:33273464, PubMed:30007416, PubMed:30799039,
CC PubMed:31142647). Interacts with nucleosomes; interaction is mainly
CC mediated via histones H2A and H2B and inactivates the
CC nucleotidyltransferase activity by blocking DNA-binding and subsequent
CC activation (PubMed:32911481, PubMed:32911480, PubMed:33051594,
CC PubMed:32911482, PubMed:32912999). Interacts with PQBP1 (via WW domain)
CC (PubMed:26046437). Interacts with TRIM14; this interaction recruits
CC USP14, leading to deubiquitinate and stabilize CGAS and promote type I
CC interferon production (PubMed:27666593, PubMed:32404352). Interacts
CC with ZCCHC3; promoting sensing of dsDNA by CGAS (PubMed:30135424).
CC Interacts with PARP1; interaction takes place in the nucleus and
CC prevents the formation of the PARP1-TIMELESS complex (PubMed:30356214).
CC {ECO:0000269|PubMed:26046437, ECO:0000269|PubMed:27666593,
CC ECO:0000269|PubMed:28363908, ECO:0000269|PubMed:30007416,
CC ECO:0000269|PubMed:30135424, ECO:0000269|PubMed:30356214,
CC ECO:0000269|PubMed:30799039, ECO:0000269|PubMed:31142647,
CC ECO:0000269|PubMed:32404352, ECO:0000269|PubMed:32911480,
CC ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32911482,
CC ECO:0000269|PubMed:32912999, ECO:0000269|PubMed:33051594,
CC ECO:0000269|PubMed:33273464}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpes virus 8/HHV-8
CC protein ORF52; this interaction inhibits cGAS enzymatic activity by
CC preventing the formation of liquid-like droplets by CGAS.
CC {ECO:0000269|PubMed:26320998, ECO:0000269|PubMed:34015248,
CC ECO:0000269|PubMed:34387695}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpes simplex virus 1
CC protein UL37; this interaction deaminates CGAS and inhibits its
CC activation. {ECO:0000269|PubMed:30092200}.
CC -!- SUBUNIT: (Microbial infection) Interacts with cytomegalovirus protein
CC UL31; this interaction promotes dissociation of DNA from CGAS, thereby
CC inhibiting the enzymatic activity of CGAS.
CC {ECO:0000269|PubMed:29937271}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpes simplex virus 1
CC tegument protein VP22 (UL49); this interaction inhibits cGAS enzymatic
CC activity by preventing the formation of liquid-like droplets by CGAS.
CC {ECO:0000269|PubMed:29793952, ECO:0000269|PubMed:34015248}.
CC -!- SUBUNIT: (Microbial infection) Interacts with herpesvirus 3 tegument
CC protein VP22 (ORF9); this interaction inhibits cGAS enzymatic activity
CC by preventing the formation of liquid-like droplets by CGAS.
CC {ECO:0000269|PubMed:34015248}.
CC -!- SUBUNIT: (Microbial infection) Interacts with human cytomegalovirus
CC proteins UL42 and UL83; these interactions result in the inhibition of
CC cGAS-STING signaling. {ECO:0000269|PubMed:29263269,
CC ECO:0000269|PubMed:31107917}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:29263269,
CC ECO:0000269|PubMed:29937271, ECO:0000269|PubMed:30270045,
CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:30811988,
CC ECO:0000269|PubMed:31299200, ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:31808743, ECO:0000269|PubMed:32792394,
CC ECO:0000269|PubMed:33230297, ECO:0000269|PubMed:33406424,
CC ECO:0000269|PubMed:33476576, ECO:0000269|PubMed:34111399}. Chromosome
CC {ECO:0000269|PubMed:30811988, ECO:0000269|PubMed:31299200,
CC ECO:0000269|PubMed:31544964, ECO:0000269|PubMed:32351706,
CC ECO:0000269|PubMed:32912999, ECO:0000269|PubMed:33051594}. Cell
CC membrane {ECO:0000269|PubMed:30827685, ECO:0000269|PubMed:32351706};
CC Peripheral membrane protein {ECO:0000269|PubMed:30827685}. Cytoplasm,
CC cytosol {ECO:0000269|PubMed:23258413, ECO:0000269|PubMed:26048138,
CC ECO:0000269|PubMed:29263269, ECO:0000269|PubMed:29937271,
CC ECO:0000269|PubMed:30799039, ECO:0000269|PubMed:30827685,
CC ECO:0000269|PubMed:31544964, ECO:0000269|PubMed:31808743,
CC ECO:0000269|PubMed:32792394, ECO:0000269|PubMed:33406424,
CC ECO:0000269|PubMed:33476576, ECO:0000269|PubMed:34111399}. Note=Mainly
CC localizes in the nucleus, and at low level in the cytosol
CC (PubMed:31808743, PubMed:31544964). On chromosomes, enriched on
CC centromeric satellite and LINE DNA repeat elements (PubMed:30811988).
CC Exported from the nucleus to the cytosol in a XPO1/CRM1 via the nuclear
CC export signal in response to DNA stimulation (PubMed:33406424). Outside
CC the nucleus, localizes at the cell membrane as a peripheral membrane
CC protein in resting conditions: association to the cell membrane is
CC mediated via binding to phosphatidylinositol 4,5-bisphosphate
CC (PtdIns(4,5)P2) (PubMed:30827685). Localization at the cell membrane is
CC required to limit the recognition of self-DNA (PubMed:30827685).
CC Following detection of double-stranded DNA (dsDNA), released from the
CC cell membrane into the cytosol in order to signal (PubMed:30827685).
CC Upon transfection with dsDNA forms punctate structures that co-localize
CC with DNA and Beclin-1 (BECN1) (PubMed:26048138). Phosphorylation at
CC Tyr-215 promotes cytosolic retention (PubMed:30356214). In response to
CC translation stress, translocates to the cytosol and associates with
CC collided ribosomes (PubMed:34111399). {ECO:0000269|PubMed:26048138,
CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:30811988,
CC ECO:0000269|PubMed:30827685, ECO:0000269|PubMed:31544964,
CC ECO:0000269|PubMed:31808743, ECO:0000269|PubMed:33406424,
CC ECO:0000269|PubMed:34111399}.
CC -!- SUBCELLULAR LOCATION: Note=(Microbial infection) Upon infection with
CC virulent M.tuberculosis forms aggregates with dsDNA, non-virulent
CC bacteria (without the ESX-1 locus) do not form these aggregates
CC (PubMed:26048138). {ECO:0000269|PubMed:26048138}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q8N884-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q8N884-2; Sequence=VSP_014388, VSP_014389;
CC -!- TISSUE SPECIFICITY: Expressed in the monocytic cell line THP1.
CC {ECO:0000269|PubMed:23258413}.
CC -!- INDUCTION: By type I interferons. {ECO:0000269|PubMed:21478870}.
CC -!- DOMAIN: Lys-187 and Leu-195 residues are specific to human and
CC destabilize the interactions with short DNA, shifting the specificity
CC toward the detection of curved long DNAs (PubMed:30007416). Lys-187 and
CC Leu-195 also restrain cGAMP production and, therefore, immune
CC activation, allowing a more fine-tuned response to pathogens
CC (PubMed:30007416). {ECO:0000269|PubMed:30007416}.
CC -!- DOMAIN: The N-terminal disordered part (1-160) binds unspecifically
CC dsDNA and expands the binding and moving range of CGAS on dsDNA
CC (PubMed:28214358, PubMed:28363908). The disordered and positively
CC charged residues enhance CGAS-DNA phase separation by increasing the
CC valencies of DNA-binding (PubMed:29976794). The N-terminus is required
CC to sense chromatin and its phosphorylation blocks its activation by
CC chromatin DNA (PubMed:33542149). When the N-terminal part (1-160) is
CC missing the protein bound to dsDNA homodimerizes (By similarity).
CC {ECO:0000250|UniProtKB:Q8C6L5, ECO:0000269|PubMed:28214358,
CC ECO:0000269|PubMed:28363908, ECO:0000269|PubMed:29976794,
CC ECO:0000269|PubMed:33542149}.
CC -!- DOMAIN: The arginine-anchor tightly binds to the canonical H2A acidic-
CC patch residues. {ECO:0000269|PubMed:32911482,
CC ECO:0000269|PubMed:32912999, ECO:0000269|PubMed:33051594}.
CC -!- PTM: The N-terminal disordered part (1-160) is phosphorylated by AURKB
CC during the G2-M transition, blocking CGAS liquid phase separation and
CC preventing activation (PubMed:33542149). Phosphorylation at Tyr-215 by
CC BLK promotes cytosolic retention (PubMed:30356214). Localizes into the
CC nucleus following dephosphorylation at Tyr-215 (PubMed:30356214).
CC Phosphorylation at Ser-435 activates the nucleotidyltransferase
CC activity (PubMed:32474700). Dephosphorylation at Ser-435 by PPP6C
CC impairs its ability to bind GTP, thereby inactivating it
CC (PubMed:32474700). Phosphorylation at Thr-68 and Ser-213 by PRKDC
CC inhibits its cyclic GMP-AMP synthase activity by impairing
CC homodimerization and activation (PubMed:33273464). Phosphorylation at
CC Ser-305 by AKT (AKT1, AKT2 or AKT3) suppresses the
CC nucleotidyltransferase activity (PubMed:26440888). Phosphorylation at
CC Ser-305 by CDK1 during mitosis leads to its inhibition, thereby
CC preventing CGAS activation by self-DNA during mitosis
CC (PubMed:32351706). Dephosphorylated at Ser-305 by protein phosphatase
CC PP1 upon mitotic exit (PubMed:32351706). {ECO:0000269|PubMed:26440888,
CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:32351706,
CC ECO:0000269|PubMed:32474700, ECO:0000269|PubMed:33273464,
CC ECO:0000269|PubMed:33542149}.
CC -!- PTM: Ubiquitinated at Lys-414 via 'Lys-48'-linked polyubiquitin chains,
CC leading to its SQSTM1-mediated autophagic degradation
CC (PubMed:27666593). Interaction with TRIM14 promotes recruitment of
CC USP14, leading to deubiquitinate Lys-414 and stabilize CGAS
CC (PubMed:27666593). Ubiquitinated at Lys-173 and Lys-384 by RNF185 via
CC 'Lys-27'-linked polyubiquitination, promoting CGAS cyclic GMP-AMP
CC synthase activity (PubMed:28273161). Monoubiquitination at Lys-347 by
CC TRIM56 promotes oligomerization and subsequent activation
CC (PubMed:29426904). Monoubiquitination by TRIM41 promotes CGAS
CC activation (PubMed:29760876). Ubiquitination at Lys-285 and Lys-479 via
CC 'Lys-48'-linked polyubiquitination promotes its degradation (By
CC similarity). Deubiquitination at Lys-285 by USP29 promotes its
CC stabilization (By similarity). Deubiquitinated by USP27X, promoting its
CC stabilization (PubMed:31534008). {ECO:0000250|UniProtKB:Q8C6L5,
CC ECO:0000269|PubMed:27666593, ECO:0000269|PubMed:28273161,
CC ECO:0000269|PubMed:29426904, ECO:0000269|PubMed:29760876,
CC ECO:0000269|PubMed:31534008}.
CC -!- PTM: Sumoylated at Lys-231 and Lys-479 by TRIM38 in uninfected cells
CC and during the early phase of viral infection, promoting its stability
CC by preventing ubiquitination at Lys-285 and Lys-479, and subsequent
CC degradation (By similarity). Desumoylated by SENP2 during the late
CC phase of viral infection (By similarity). Sumoylation at Lys-347, Lys-
CC 384 and Lys-394 prevents DNA-binding, oligomerization and
CC nucleotidyltransferase activity (By similarity). Desumoylation at Lys-
CC 347, Lys-384 and Lys-394 by SENP7 relieves inhibition and activates
CC CGAS (By similarity). {ECO:0000250|UniProtKB:Q8C6L5}.
CC -!- PTM: Polyglutamylated by TTLL6 at Glu-286, leading to impair DNA-
CC binding activity. Monoglutamylated at Glu-314 by TTLL4, leading to
CC impair the nucleotidyltransferase activity. Deglutamylated by
CC AGBL5/CCP5 and AGBL6/CCP6. {ECO:0000250|UniProtKB:Q8C6L5}.
CC -!- PTM: Acetylation at Lys-384, Lys-394 and Lys-414 inhibits the cyclic
CC GMP-AMP synthase activity (PubMed:30799039). Deacetylated upon
CC cytosolic DNA challenge such as viral infections (PubMed:30799039).
CC Acetylation can be mediated by aspirin (acetylsalicylate) drug, which
CC directly acetylates CGAS (PubMed:30799039). Acetylation by aspirin
CC efficiently inhibits CGAS-mediated immune responses and is able to
CC suppress self-DNA-induced autoimmunity (PubMed:30799039). Acetylation
CC at Lys-47, Lys-56, Lys-62 and Lys-83 by KAT5 increases the cyclic GMP-
CC AMP synthase activity by promoting DNA-binding and subsequent
CC activation (PubMed:32817552). {ECO:0000269|PubMed:30799039,
CC ECO:0000269|PubMed:32817552}.
CC -!- PTM: Proteolytically cleaved by apoptotic caspases during apoptosis,
CC leading to its inactivation (PubMed:30878284). The damage of the
CC nucleus and the mitochondria during apoptosis leads to leakage of
CC nuclear and mitochondrial DNA, which activate CGAS: cleavage and
CC inactivation during apoptosis in required to prevent cytokine
CC overproduction (By similarity). Cleaved by CASP3 at Asp-319 during
CC virus-induced apoptosis, thereby inactivating it and preventing
CC cytokine overproduction (PubMed:30878284). Cleaved by CASP1 at Asp-140
CC and Asp-157 upon DNA virus infection; the cleavage impairs cGAMP
CC production (PubMed:28314590). Also cleaved by the pyroptotic CASP4 and
CC CASP5 during non-canonical inflammasome activation; they don't cut at
CC the same sites than CASP1 (PubMed:28314590).
CC {ECO:0000250|UniProtKB:Q8C6L5, ECO:0000269|PubMed:28314590,
CC ECO:0000269|PubMed:30878284}.
CC -!- PTM: (Microbial infection) Deamidated on 'Asn-210' by herpes simplex
CC virus 1 protein UL37. This modification significantly reduces CGAS-
CC dependent cGAMP production and innate immune signaling induced by
CC dsDNA. {ECO:0000269|PubMed:30092200}.
CC -!- PTM: (Microbial infection) Degraded by an autophagy-mediated mechanism
CC in presence of Chikungunya virus capsid protein.
CC {ECO:0000269|PubMed:33057424}.
CC -!- MISCELLANEOUS: The cGAS-STING signaling pathway drives sterile
CC inflammation leading to type I interferon immunopathology in severe
CC COVID-19 disease caused by SARS-CoV-2 virus infection
CC (PubMed:35045565). Tissue damages in the lung and skin lesions are
CC caused by activation of the cGAS-STING signaling leading to aberrant
CC inflammation (PubMed:35045565). Endothelial cell damage is also caused
CC by activation of the cGAS-STING pathway: SARS-CoV-2 infection triggers
CC mitochondrial DNA release into the cytosol (PubMed:35045565). Released
CC mitochondrial DNA is then detected by CGAS, leading to activation of
CC the cGAS-STING pathway, triggering type-I interferon production and
CC autoinflammation (PubMed:35045565). {ECO:0000269|PubMed:35045565}.
CC -!- SIMILARITY: Belongs to the mab-21 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH12928.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; KC294566; AGB51853.1; -; mRNA.
DR EMBL; AK097148; BAC04965.1; -; mRNA.
DR EMBL; AC019205; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL603910; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC012928; AAH12928.1; ALT_INIT; mRNA.
DR EMBL; BC108714; AAI08715.1; -; mRNA.
DR EMBL; BC113606; AAI13607.1; -; mRNA.
DR EMBL; BC113608; AAI13609.1; -; mRNA.
DR EMBL; BC143694; AAI43695.1; -; mRNA.
DR CCDS; CCDS4978.1; -. [Q8N884-1]
DR RefSeq; NP_612450.2; NM_138441.2. [Q8N884-1]
DR PDB; 4KM5; X-ray; 2.50 A; A=157-522.
DR PDB; 4LEV; X-ray; 1.95 A; A/B=157-522.
DR PDB; 4LEW; X-ray; 2.04 A; A/B=157-522.
DR PDB; 4MKP; X-ray; 1.95 A; A=161-522.
DR PDB; 4O67; X-ray; 2.44 A; A/B=161-522.
DR PDB; 4O68; X-ray; 2.44 A; A=147-522.
DR PDB; 4O69; X-ray; 2.25 A; A=161-522.
DR PDB; 5V8O; X-ray; 3.10 A; A/B=161-522.
DR PDB; 5VDO; X-ray; 3.22 A; A/B=161-522.
DR PDB; 5VDP; X-ray; 2.30 A; A/B=161-522.
DR PDB; 5VDQ; X-ray; 3.25 A; A/B=161-522.
DR PDB; 5VDR; X-ray; 3.04 A; A/B=161-522.
DR PDB; 5VDS; X-ray; 2.77 A; A/B=161-522.
DR PDB; 5VDT; X-ray; 2.58 A; A/B=161-522.
DR PDB; 5VDU; X-ray; 2.73 A; A/B=161-522.
DR PDB; 5VDV; X-ray; 3.00 A; A/B=161-522.
DR PDB; 5VDW; X-ray; 2.71 A; A/B=161-522.
DR PDB; 6CT9; X-ray; 2.26 A; A=157-522.
DR PDB; 6CTA; X-ray; 2.78 A; A=157-522.
DR PDB; 6EDB; X-ray; 3.21 A; A/B=157-522.
DR PDB; 6EDC; X-ray; 2.71 A; A=157-522.
DR PDB; 6LRC; X-ray; 1.83 A; A/B=157-522.
DR PDB; 6LRE; X-ray; 2.65 A; A/B=157-522.
DR PDB; 6LRI; X-ray; 2.50 A; A/B=157-522.
DR PDB; 6LRJ; X-ray; 3.00 A; A/B=157-522.
DR PDB; 6LRK; X-ray; 2.25 A; A/B=157-522.
DR PDB; 6LRL; X-ray; 2.65 A; A/B=157-522.
DR PDB; 6MJU; X-ray; 2.45 A; A=152-522.
DR PDB; 6MJW; X-ray; 2.40 A; A=152-522.
DR PDB; 6MJX; X-ray; 2.60 A; A=152-522.
DR PDB; 6NAO; X-ray; 3.23 A; A/B=161-522.
DR PDB; 6NFG; X-ray; 2.76 A; A/B=161-522.
DR PDB; 6NFO; X-ray; 2.93 A; A/B=161-522.
DR PDB; 6O47; X-ray; 2.20 A; A=152-522.
DR PDB; 6Y5D; EM; 4.10 A; K/L=161-522.
DR PDB; 6Y5E; EM; 3.15 A; K=161-522.
DR PDB; 7C0M; EM; 3.90 A; K/k=151-522.
DR PDB; 7CCQ; EM; 3.80 A; K=157-522.
DR PDB; 7CCR; EM; 4.90 A; K/V=157-522.
DR PDBsum; 4KM5; -.
DR PDBsum; 4LEV; -.
DR PDBsum; 4LEW; -.
DR PDBsum; 4MKP; -.
DR PDBsum; 4O67; -.
DR PDBsum; 4O68; -.
DR PDBsum; 4O69; -.
DR PDBsum; 5V8O; -.
DR PDBsum; 5VDO; -.
DR PDBsum; 5VDP; -.
DR PDBsum; 5VDQ; -.
DR PDBsum; 5VDR; -.
DR PDBsum; 5VDS; -.
DR PDBsum; 5VDT; -.
DR PDBsum; 5VDU; -.
DR PDBsum; 5VDV; -.
DR PDBsum; 5VDW; -.
DR PDBsum; 6CT9; -.
DR PDBsum; 6CTA; -.
DR PDBsum; 6EDB; -.
DR PDBsum; 6EDC; -.
DR PDBsum; 6LRC; -.
DR PDBsum; 6LRE; -.
DR PDBsum; 6LRI; -.
DR PDBsum; 6LRJ; -.
DR PDBsum; 6LRK; -.
DR PDBsum; 6LRL; -.
DR PDBsum; 6MJU; -.
DR PDBsum; 6MJW; -.
DR PDBsum; 6MJX; -.
DR PDBsum; 6NAO; -.
DR PDBsum; 6NFG; -.
DR PDBsum; 6NFO; -.
DR PDBsum; 6O47; -.
DR PDBsum; 6Y5D; -.
DR PDBsum; 6Y5E; -.
DR PDBsum; 7C0M; -.
DR PDBsum; 7CCQ; -.
DR PDBsum; 7CCR; -.
DR AlphaFoldDB; Q8N884; -.
DR SASBDB; Q8N884; -.
DR SMR; Q8N884; -.
DR BioGRID; 125408; 280.
DR IntAct; Q8N884; 12.
DR MINT; Q8N884; -.
DR STRING; 9606.ENSP00000359339; -.
DR BindingDB; Q8N884; -.
DR ChEMBL; CHEMBL4105728; -.
DR GuidetoPHARMACOLOGY; 3165; -.
DR iPTMnet; Q8N884; -.
DR PhosphoSitePlus; Q8N884; -.
DR BioMuta; MB21D1; -.
DR DMDM; 68565218; -.
DR EPD; Q8N884; -.
DR jPOST; Q8N884; -.
DR MassIVE; Q8N884; -.
DR MaxQB; Q8N884; -.
DR PaxDb; Q8N884; -.
DR PeptideAtlas; Q8N884; -.
DR PRIDE; Q8N884; -.
DR ProteomicsDB; 72382; -. [Q8N884-1]
DR ProteomicsDB; 72383; -. [Q8N884-2]
DR Antibodypedia; 31341; 221 antibodies from 32 providers.
DR DNASU; 115004; -.
DR Ensembl; ENST00000370315.4; ENSP00000359339.3; ENSG00000164430.17. [Q8N884-1]
DR Ensembl; ENST00000370318.5; ENSP00000359342.1; ENSG00000164430.17. [Q8N884-2]
DR GeneID; 115004; -.
DR KEGG; hsa:115004; -.
DR MANE-Select; ENST00000370315.4; ENSP00000359339.3; NM_138441.3; NP_612450.2.
DR UCSC; uc003pgx.2; human. [Q8N884-1]
DR CTD; 115004; -.
DR DisGeNET; 115004; -.
DR GeneCards; CGAS; -.
DR HGNC; HGNC:21367; CGAS.
DR HPA; ENSG00000164430; Tissue enhanced (bone).
DR MIM; 613973; gene.
DR neXtProt; NX_Q8N884; -.
DR OpenTargets; ENSG00000164430; -.
DR PharmGKB; PA134956015; -.
DR VEuPathDB; HostDB:ENSG00000164430; -.
DR eggNOG; KOG3963; Eukaryota.
DR GeneTree; ENSGT01050000244827; -.
DR HOGENOM; CLU_040428_2_0_1; -.
DR InParanoid; Q8N884; -.
DR OMA; CLRTEKL; -.
DR OrthoDB; 759341at2759; -.
DR PhylomeDB; Q8N884; -.
DR TreeFam; TF331255; -.
DR BRENDA; 2.7.7.86; 2681.
DR PathwayCommons; Q8N884; -.
DR Reactome; R-HSA-1834941; STING mediated induction of host immune responses.
DR SignaLink; Q8N884; -.
DR SIGNOR; Q8N884; -.
DR BioGRID-ORCS; 115004; 10 hits in 1061 CRISPR screens.
DR ChiTaRS; MB21D1; human.
DR GenomeRNAi; 115004; -.
DR Pharos; Q8N884; Tchem.
DR PRO; PR:Q8N884; -.
DR Proteomes; UP000005640; Chromosome 6.
DR RNAct; Q8N884; protein.
DR Bgee; ENSG00000164430; Expressed in pancreatic ductal cell and 172 other tissues.
DR Genevisible; Q8N884; HS.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0061501; F:2',3'-cyclic GMP-AMP synthase activity; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0003682; F:chromatin binding; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:UniProtKB.
DR GO; GO:0003690; F:double-stranded DNA binding; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0031491; F:nucleosome binding; IDA:UniProtKB.
DR GO; GO:0005546; F:phosphatidylinositol-4,5-bisphosphate binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:UniProtKB.
DR GO; GO:0071360; P:cellular response to exogenous dsRNA; IBA:GO_Central.
DR GO; GO:0019934; P:cGMP-mediated signaling; IDA:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IEA:Ensembl.
DR GO; GO:0006281; P:DNA repair; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:2000042; P:negative regulation of double-strand break repair via homologous recombination; IDA:UniProtKB.
DR GO; GO:0038001; P:paracrine signaling; IDA:UniProtKB.
DR GO; GO:2000774; P:positive regulation of cellular senescence; ISS:UniProtKB.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IDA:UniProtKB.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IEA:Ensembl.
DR GO; GO:0050863; P:regulation of T cell activation; IEA:Ensembl.
DR DisProt; DP02876; -.
DR InterPro; IPR024810; Mab-21_dom.
DR Pfam; PF03281; Mab-21; 1.
DR SMART; SM01265; Mab-21; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Antiviral defense;
KW ATP-binding; Cell membrane; Chromosome; Cytoplasm; DNA damage; DNA repair;
KW DNA-binding; GTP-binding; Host-virus interaction; Immunity;
KW Innate immunity; Isopeptide bond; Lipid-binding; Magnesium; Membrane;
KW Metal-binding; Nucleotide-binding; Nucleotidyltransferase; Nucleus;
KW Phosphoprotein; Reference proteome; Transferase; Ubl conjugation; Zinc.
FT CHAIN 1..522
FT /note="Cyclic GMP-AMP synthase"
FT /id="PRO_0000089543"
FT REGION 1..160
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:28363908"
FT REGION 1..144
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 64..75
FT /note="Required for association with the cell membrane"
FT /evidence="ECO:0000269|PubMed:30827685"
FT REGION 120..160
FT /note="Required for activation upon DNA viral infection"
FT /evidence="ECO:0000269|PubMed:28314590"
FT REGION 173..215
FT /note="DNA-binding"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0000305|PubMed:23707061, ECO:0007744|PDB:6CTA"
FT REGION 341..382
FT /note="Interaction with collided ribosomes"
FT /evidence="ECO:0000269|PubMed:34111399"
FT REGION 384..407
FT /note="DNA-binding"
FT /evidence="ECO:0000305|PubMed:23707061"
FT MOTIF 169..174
FT /note="Nuclear export signal"
FT /evidence="ECO:0000269|PubMed:33406424"
FT MOTIF 295..305
FT /note="Nuclear localization signal"
FT /evidence="ECO:0000269|PubMed:30356214"
FT MOTIF 299..302
FT /note="KRKR-loop"
FT /evidence="ECO:0000269|PubMed:31142647"
FT MOTIF 427..429
FT /note="KKH-loop"
FT /evidence="ECO:0000269|PubMed:31142647"
FT BINDING 211
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT BINDING 213
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0007744|PDB:6CTA"
FT BINDING 225..227
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0007744|PDB:6CTA"
FT BINDING 225
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0000305|PubMed:23722159, ECO:0000305|PubMed:26229115,
FT ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA"
FT BINDING 227
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:31113940, ECO:0007744|PDB:4O67,
FT ECO:0007744|PDB:6MJX"
FT BINDING 227
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0000305|PubMed:23722159, ECO:0000305|PubMed:26229115,
FT ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA"
FT BINDING 319
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:31113940, ECO:0007744|PDB:4O67,
FT ECO:0007744|PDB:6MJX"
FT BINDING 319
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000305|PubMed:24462292"
FT BINDING 319
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /ligand_note="catalytic"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA"
FT BINDING 362
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:31113940, ECO:0007744|PDB:4O67,
FT ECO:0007744|PDB:6MJX"
FT BINDING 376..383
FT /ligand="GTP"
FT /ligand_id="ChEBI:CHEBI:37565"
FT /evidence="ECO:0000305|PubMed:24462292"
FT BINDING 376
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:31113940, ECO:0007744|PDB:4O67,
FT ECO:0007744|PDB:6MJX"
FT BINDING 380..383
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0007744|PDB:6CTA"
FT BINDING 390
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:28940468,
FT ECO:0000269|PubMed:30007416, ECO:0000269|PubMed:31113940,
FT ECO:0000269|PubMed:31142647, ECO:0000269|PubMed:32911482,
FT ECO:0000269|PubMed:32912999, ECO:0007744|PDB:5V8O,
FT ECO:0007744|PDB:5VDO, ECO:0007744|PDB:5VDP,
FT ECO:0007744|PDB:5VDQ, ECO:0007744|PDB:5VDR,
FT ECO:0007744|PDB:5VDS, ECO:0007744|PDB:5VDT,
FT ECO:0007744|PDB:5VDU, ECO:0007744|PDB:5VDV,
FT ECO:0007744|PDB:5VDW, ECO:0007744|PDB:6CT9,
FT ECO:0007744|PDB:6CTA, ECO:0007744|PDB:6EDB,
FT ECO:0007744|PDB:6EDC, ECO:0007744|PDB:6MJU,
FT ECO:0007744|PDB:6MJW, ECO:0007744|PDB:6MJX,
FT ECO:0007744|PDB:6NAO, ECO:0007744|PDB:6NFG,
FT ECO:0007744|PDB:6NFO, ECO:0007744|PDB:6Y5D,
FT ECO:0007744|PDB:6Y5E, ECO:0007744|PDB:7C0M"
FT BINDING 396
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:28940468,
FT ECO:0000269|PubMed:30007416, ECO:0000269|PubMed:31113940,
FT ECO:0000269|PubMed:31142647, ECO:0000269|PubMed:32459092,
FT ECO:0000269|PubMed:32911482, ECO:0000269|PubMed:32912999,
FT ECO:0007744|PDB:5V8O, ECO:0007744|PDB:5VDO,
FT ECO:0007744|PDB:5VDP, ECO:0007744|PDB:5VDQ,
FT ECO:0007744|PDB:5VDR, ECO:0007744|PDB:5VDS,
FT ECO:0007744|PDB:5VDT, ECO:0007744|PDB:5VDU,
FT ECO:0007744|PDB:5VDV, ECO:0007744|PDB:5VDW,
FT ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA,
FT ECO:0007744|PDB:6EDB, ECO:0007744|PDB:6EDC,
FT ECO:0007744|PDB:6LRC, ECO:0007744|PDB:6MJU,
FT ECO:0007744|PDB:6MJW, ECO:0007744|PDB:6MJX,
FT ECO:0007744|PDB:6NAO, ECO:0007744|PDB:6NFG,
FT ECO:0007744|PDB:6NFO, ECO:0007744|PDB:6O47,
FT ECO:0007744|PDB:6Y5D, ECO:0007744|PDB:6Y5E,
FT ECO:0007744|PDB:7C0M"
FT BINDING 397
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:28940468,
FT ECO:0000269|PubMed:30007416, ECO:0000269|PubMed:31113940,
FT ECO:0000269|PubMed:31142647, ECO:0000269|PubMed:32459092,
FT ECO:0000269|PubMed:32911482, ECO:0000269|PubMed:32912999,
FT ECO:0007744|PDB:5V8O, ECO:0007744|PDB:5VDO,
FT ECO:0007744|PDB:5VDP, ECO:0007744|PDB:5VDQ,
FT ECO:0007744|PDB:5VDR, ECO:0007744|PDB:5VDS,
FT ECO:0007744|PDB:5VDT, ECO:0007744|PDB:5VDU,
FT ECO:0007744|PDB:5VDV, ECO:0007744|PDB:5VDW,
FT ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA,
FT ECO:0007744|PDB:6EDB, ECO:0007744|PDB:6EDC,
FT ECO:0007744|PDB:6LRC, ECO:0007744|PDB:6MJU,
FT ECO:0007744|PDB:6MJW, ECO:0007744|PDB:6MJX,
FT ECO:0007744|PDB:6NAO, ECO:0007744|PDB:6NFG,
FT ECO:0007744|PDB:6NFO, ECO:0007744|PDB:6O47,
FT ECO:0007744|PDB:6Y5D, ECO:0007744|PDB:6Y5E,
FT ECO:0007744|PDB:7C0M"
FT BINDING 404
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:24332030, ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:28934246, ECO:0000269|PubMed:28940468,
FT ECO:0000269|PubMed:30007416, ECO:0000269|PubMed:31113940,
FT ECO:0000269|PubMed:31142647, ECO:0000269|PubMed:32459092,
FT ECO:0000269|PubMed:32911482, ECO:0000269|PubMed:32912999,
FT ECO:0007744|PDB:5V8O, ECO:0007744|PDB:5VDO,
FT ECO:0007744|PDB:5VDP, ECO:0007744|PDB:5VDQ,
FT ECO:0007744|PDB:5VDR, ECO:0007744|PDB:5VDS,
FT ECO:0007744|PDB:5VDT, ECO:0007744|PDB:5VDU,
FT ECO:0007744|PDB:5VDV, ECO:0007744|PDB:5VDW,
FT ECO:0007744|PDB:6CT9, ECO:0007744|PDB:6CTA,
FT ECO:0007744|PDB:6EDB, ECO:0007744|PDB:6EDC,
FT ECO:0007744|PDB:6LRC, ECO:0007744|PDB:6MJU,
FT ECO:0007744|PDB:6MJW, ECO:0007744|PDB:6MJX,
FT ECO:0007744|PDB:6NAO, ECO:0007744|PDB:6NFG,
FT ECO:0007744|PDB:6NFO, ECO:0007744|PDB:6O47,
FT ECO:0007744|PDB:6Y5D, ECO:0007744|PDB:6Y5E,
FT ECO:0007744|PDB:7C0M"
FT BINDING 414
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0007744|PDB:6CTA"
FT BINDING 435..439
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:30007416,
FT ECO:0000305|PubMed:24462292, ECO:0007744|PDB:6CTA"
FT SITE 140..141
FT /note="Cleavage; by CASP1"
FT /evidence="ECO:0000269|PubMed:28314590"
FT SITE 157..158
FT /note="Cleavage; by CASP1"
FT /evidence="ECO:0000269|PubMed:28314590"
FT SITE 187
FT /note="Important for preferential detection of curved long
FT DNA"
FT /evidence="ECO:0000269|PubMed:30007416"
FT SITE 195
FT /note="Important for preferential detection of curved long
FT DNA"
FT /evidence="ECO:0000269|PubMed:30007416"
FT SITE 255
FT /note="Arginine-anchor"
FT /evidence="ECO:0000269|PubMed:32911482,
FT ECO:0000269|PubMed:32912999, ECO:0000269|PubMed:33051594"
FT SITE 319..320
FT /note="Cleavage; by CASP3"
FT /evidence="ECO:0000269|PubMed:30878284"
FT MOD_RES 7
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:30799039,
FT ECO:0007744|PubMed:19608861"
FT MOD_RES 13
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33542149"
FT MOD_RES 21
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 37
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33542149"
FT MOD_RES 47
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 50
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:30799039,
FT ECO:0000269|PubMed:32817552"
FT MOD_RES 56
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 62
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 63
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 64
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33542149"
FT MOD_RES 68
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:33273464,
FT ECO:0000269|PubMed:33542149"
FT MOD_RES 82
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 83
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:32817552"
FT MOD_RES 91
FT /note="Phosphothreonine"
FT /evidence="ECO:0000269|PubMed:32474700,
FT ECO:0000269|PubMed:33542149"
FT MOD_RES 98
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:32474700"
FT MOD_RES 116
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33542149"
FT MOD_RES 129
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33542149"
FT MOD_RES 143
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33542149,
FT ECO:0007744|PubMed:20068231"
FT MOD_RES 210
FT /note="(Microbial infection) Deamidated asparagine; by
FT herpes simplex virus 1/HHV-1 UL37"
FT /evidence="ECO:0000269|PubMed:30092200"
FT MOD_RES 213
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:33273464"
FT MOD_RES 215
FT /note="Phosphotyrosine; by BLK"
FT /evidence="ECO:0000269|PubMed:30356214"
FT MOD_RES 286
FT /note="5-glutamyl polyglutamate"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT MOD_RES 305
FT /note="Phosphoserine; by CDK1 and PKB"
FT /evidence="ECO:0000269|PubMed:26440888,
FT ECO:0000269|PubMed:32351706, ECO:0000269|PubMed:33542149"
FT MOD_RES 314
FT /note="5-glutamyl glutamate"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT MOD_RES 384
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:30799039"
FT MOD_RES 389
FT /note="(Microbial infection) Deamidated asparagine; by
FT herpes simplex virus 1/HHV-1 UL37"
FT /evidence="ECO:0000269|PubMed:30092200"
FT MOD_RES 392
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:30799039"
FT MOD_RES 394
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:30799039"
FT MOD_RES 414
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000269|PubMed:30799039,
FT ECO:0007744|PubMed:19608861"
FT MOD_RES 434
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:32474700"
FT MOD_RES 435
FT /note="Phosphoserine"
FT /evidence="ECO:0000269|PubMed:32474700"
FT MOD_RES 451
FT /note="(Microbial infection) Deamidated glutamine; by
FT herpes simplex virus 1/HHV-1 UL37"
FT /evidence="ECO:0000269|PubMed:30092200"
FT MOD_RES 454
FT /note="(Microbial infection) Deamidated glutamine; by
FT herpes simplex virus 1/HHV-1 UL37"
FT /evidence="ECO:0000269|PubMed:30092200"
FT CROSSLNK 173
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:28273161"
FT CROSSLNK 231
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000269|PubMed:27637147"
FT CROSSLNK 285
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:27637147"
FT CROSSLNK 347
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT CROSSLNK 347
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT CROSSLNK 384
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT CROSSLNK 384
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:28273161"
FT CROSSLNK 394
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250|UniProtKB:Q8C6L5"
FT CROSSLNK 414
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:27666593"
FT CROSSLNK 479
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000269|PubMed:27637147"
FT CROSSLNK 479
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000269|PubMed:27637147"
FT VAR_SEQ 445..447
FT /note="VCT -> RLY (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_014388"
FT VAR_SEQ 448..522
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_014389"
FT VARIANT 35
FT /note="T -> N (in dbSNP:rs9352000)"
FT /evidence="ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:15489334"
FT /id="VAR_050811"
FT VARIANT 261
FT /note="P -> H (in dbSNP:rs610913)"
FT /evidence="ECO:0000269|PubMed:15489334"
FT /id="VAR_033677"
FT VARIANT 303
FT /note="G -> E (found in patients with tumors; dominant
FT mutation; reduced nucleotidyltransferase activity)"
FT /evidence="ECO:0000269|PubMed:31142647"
FT /id="VAR_085524"
FT VARIANT 432
FT /note="K -> T (found in patients with uterine endometrioid
FT carcinoma, reduced nucleotidyltransferase activity)"
FT /evidence="ECO:0000269|PubMed:31142647"
FT /id="VAR_085525"
FT MUTAGEN 7
FT /note="K->Q: Acetylation-mimetic mutant; no effect."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 7
FT /note="K->R: No effect."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 13
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with E-18, D-23, E-35, D-37, D-57, D-59, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 18
FT /note="T->E: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, D-23, E-35, D-37, D-57, D-59, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 23
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, E-35, D-37, D-57, D-59, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 33
FT /note="D->A: No effect on type I IFN and RSAD2 induction.
FT No effect on cleavage by CASP1. No effect on cleavage by
FT CASP1; when associated with A-67; A-90 and A-95. Highly
FT decreases cleavage by CASP1 and enhances RSAD2 induction
FT upon DNA virus infection; when associated with A-67; A-90;
FT A-95 and A-140. Abolishes cleavage by CASP1 and enhances
FT RSAD2 induction upon DNA virus infection; when associated
FT with A-67; A-90; A-95; A-140 and A-157."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 35
FT /note="T->E: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, D-37, D-57, D-59, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 37
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-57, D-59, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 47
FT /note="K->R: Decreased acetylation by KAT5, leading to
FT decreased stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:32817552"
FT MUTAGEN 50
FT /note="K->Q: Acetylation-mimetic mutant; no effect."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 50
FT /note="K->R: No effect."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 56
FT /note="K->R: Decreased acetylation by KAT5, leading to
FT decreased stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:32817552"
FT MUTAGEN 57
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-59, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 59
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-64,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 62
FT /note="K->R: Decreased acetylation by KAT5, leading to
FT decreased stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:32817552"
FT MUTAGEN 64
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 67
FT /note="D->A: No effect on type I IFN and RSAD2 induction.
FT No effect on cleavage by CASP1; when associated with A-33;
FT A-90 and A-95. Highly decreases cleavage by CASP1 and
FT enhances RSAD2 induction upon DNA virus infection; when
FT associated with A-33; A-90; A-95 and A-140. Abolishes
FT cleavage by CASP1 and enhances RSAD2 induction upon DNA
FT virus infection; when associated with A-33; A-90; A-95; A-
FT 140 and A-157."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 68
FT /note="T->E: Phospho-mimetic mutant; decreased
FT nucleotidyltransferase activity. In 20DE phospho-mimetic
FT mutant; causes inactivation of nucleotidyltransferase
FT activity; when associates with D-13, E-18, D-23, E-35, D-
FT 37, D-57, D-59, D-64, E-77, E-91, D-94, E-97, D-98, D-116,
FT D-120, D-129, E-130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33273464,
FT ECO:0000269|PubMed:33542149"
FT MUTAGEN 71..75
FT /note="RPPVR->EPPVE: Abolished binding to
FT phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) and
FT abolished association with the cell membrane."
FT /evidence="ECO:0000269|PubMed:30827685"
FT MUTAGEN 77
FT /note="T->E: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-91, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 83
FT /note="K->R: Decreased acetylation by KAT5, leading to
FT decreased stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:32817552"
FT MUTAGEN 90
FT /note="D->A: No effect on type I IFN and RSAD2 induction.
FT No effect on cleavage by CASP1; when associated with A-33;
FT A-67 and A-95. Highly decreases cleavage by CASP1 and
FT enhances RSAD2 induction upon DNA virus infection; when
FT associated with A-33; A-67; A-95 and A-140. Abolishes
FT cleavage by CASP1 and enhances RSAD2 induction upon DNA
FT virus infection; when associated with A-33; A-67; A-95; A-
FT 140 and A-157."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 91
FT /note="T->E: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, D-94, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 94
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, E-97, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 95
FT /note="D->A: No effect on type I IFN and RSAD2 induction.
FT No effect on cleavage by CASP1; when associated with A-33;
FT A-67 and A-90. Highly decreases cleavage by CASP1 and
FT enhances RSAD2 induction upon DNA virus infection; when
FT associated with A-33; A-67; A-90 and A-140. Abolishes
FT cleavage by CASP1 and enhances RSAD2 induction upon DNA
FT virus infection; when associated with A-33; A-67; A-90; A-
FT 140 and A-157."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 97
FT /note="T->E: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, D-98, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 98
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-116, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 116
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-98, D-120, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 120
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-129, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 129
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, E-
FT 130, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 130
FT /note="T->E: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-
FT 129, D-143 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 140
FT /note="D->A: Highly decreases cleavage by CASP1 and
FT enhances type I IFN and RSAD2 induction upon DNA virus
FT infection. Abolishes cleavage by CASP1, enhances RSAD2
FT induction upon DNA virus infection but no effect on
FT cleavage by CASP5; when associated with A-157. Highly
FT decreases cleavage by CASP1 and enhances RSAD2 induction
FT upon DNA virus infection; when associated with A-33; A-67;
FT A-90 and A-95. Abolishes cleavage by CASP1 and enhances
FT RSAD2 induction upon DNA virus infection; when associated
FT with A-33; A-67; A-90; A-95 and A-157."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 140
FT /note="D->H: Highly decreases cleavage by CASP1 and
FT enhances type I IFN and RSAD2 induction upon DNA virus
FT infection."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 143
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-
FT 129, E-130 and D-149."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 149
FT /note="S->D: In 20DE phospho-mimetic mutant; causes
FT inactivation of nucleotidyltransferase activity; when
FT associates with D-13, E-18, D-23, E-35, D-37, D-57, D-59,
FT D-64, E-68, E-77, E-91, D-94, E-97, D-98, D-116, D-120, D-
FT 129, E-130 and D-143."
FT /evidence="ECO:0000269|PubMed:33542149"
FT MUTAGEN 157
FT /note="D->A: No effect on type I IFN and RSAD2 induction.
FT Highly decreases cleavage by CASP1 and enhances type I IFN
FT and enhances RSAD2 induction upon DNA virus infection.
FT Abolishes cleavage by CASP1, enhances RSAD2 induction upon
FT DNA virus infection but no effect on cleavage by CASP5;
FT when associated with A-140. Abolishes cleavage by CASP1;
FT when associated with A-33; A-67; A-90; A-95 and A-140."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 157
FT /note="D->H: Highly decreases cleavage by CASP1 and
FT enhances type I IFN and enhances RSAD2 induction upon DNA
FT virus infection."
FT /evidence="ECO:0000269|PubMed:28314590"
FT MUTAGEN 169..174
FT /note="LEKLKL->AAAAAA: Abolished export from the nucleus to
FT the cytosol in response to DNA stimulation."
FT /evidence="ECO:0000269|PubMed:33406424"
FT MUTAGEN 171..174
FT /note="Missing: Abolishes DNA-binding but does not affect
FT translocation to the nucleus following treatment with
FT etoposide; when associated with A-407."
FT /evidence="ECO:0000269|PubMed:30356214"
FT MUTAGEN 171
FT /note="K->A: No effect on stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23707061"
FT MUTAGEN 172
FT /note="L->A: Impaired type-I interferon production in
FT response to DNA stimulation."
FT /evidence="ECO:0000269|PubMed:33406424"
FT MUTAGEN 173
FT /note="K->A: Strongly reduces enzyme activity and
FT stimulation of interferon production; when associated with
FT A-176. No effect on stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:23722159, ECO:0000269|PubMed:24116191"
FT MUTAGEN 173
FT /note="K->E: Strongly reduces stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:23722159"
FT MUTAGEN 173
FT /note="K->R: Strongly decreased ubiquitination by RNF185;
FT when associated with R-384."
FT /evidence="ECO:0000269|PubMed:28273161"
FT MUTAGEN 174
FT /note="L->N: Strongly reduces enzyme activity and
FT stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:23722159,
FT ECO:0000269|PubMed:24116191"
FT MUTAGEN 176
FT /note="R->A: Strongly reduces enzyme activity and
FT stimulation of interferon production; when associated with
FT A-173."
FT /evidence="ECO:0000269|PubMed:23722159"
FT MUTAGEN 187
FT /note="K->N: Induces alteration of the DNA-binding surface
FT and leads to increased synthesis of cyclic GMP-AMP (cGAMP);
FT when associated with R-195."
FT /evidence="ECO:0000269|PubMed:30007416"
FT MUTAGEN 195
FT /note="L->R: Induces alteration of the DNA-binding surface
FT and leads to increased synthesis of cyclic GMP-AMP (cGAMP);
FT when associated with N-187."
FT /evidence="ECO:0000269|PubMed:30007416"
FT MUTAGEN 210..214
FT /note="NTGSY->ATGSA: Abolishes DNA-binding but does not
FT affect translocation to the nucleus following treatment
FT with etoposide; when associated with A-384."
FT /evidence="ECO:0000269|PubMed:30356214"
FT MUTAGEN 210
FT /note="N->D: More than 75% inhibition of interferon beta
FT production."
FT /evidence="ECO:0000269|PubMed:30092200"
FT MUTAGEN 211
FT /note="T->Q: Abolishes enzyme activity; when associated
FT with I-376 and I-436."
FT /evidence="ECO:0000269|PubMed:25131990"
FT MUTAGEN 212..213
FT /note="GS->AA: Abolishes enzyme activity. Abolishes
FT stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:23722159"
FT MUTAGEN 213
FT /note="S->D: Phospho-mimetic mutant; decreased
FT nucleotidyltransferase activity."
FT /evidence="ECO:0000269|PubMed:33273464"
FT MUTAGEN 215
FT /note="Y->A: Strongly reduced tyrosine phosphorylation."
FT /evidence="ECO:0000269|PubMed:30356214"
FT MUTAGEN 215
FT /note="Y->E: Phosphomimetic mutant; reduced translocation
FT to the nucleus following treatment with etoposide."
FT /evidence="ECO:0000269|PubMed:30356214"
FT MUTAGEN 225..227
FT /note="EFD->AFA: Abolishes enzyme activity and stimulation
FT of interferon production. Does not affect subcellular
FT location to the nucleus and cytosol."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:23722159, ECO:0000269|PubMed:26229115,
FT ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:31299200,
FT ECO:0000269|PubMed:31544964"
FT MUTAGEN 231
FT /note="K->R: Reduced sumoylation."
FT /evidence="ECO:0000269|PubMed:27637147"
FT MUTAGEN 236
FT /note="R->E: Abolishes stimulation of interferon
FT production; when associated with E-254 and E-327. Strongly
FT decreased interaction with nucleosomes and tethering to
FT chromatin, leading to constitutive activation in the
FT absence of DNA."
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:31808743, ECO:0000269|PubMed:32911480,
FT ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:32911482,
FT ECO:0000269|PubMed:33051594"
FT MUTAGEN 246
FT /note="R->E: Does not affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 252
FT /note="K->E: Does not affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 254
FT /note="K->A: Strongly decreased interaction with histones
FT H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594"
FT MUTAGEN 254
FT /note="K->E: Abolishes stimulation of interferon
FT production; when associated with E-236 and E-327. Abolished
FT interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:32911481"
FT MUTAGEN 255
FT /note="R->E: Abolished interaction with nucleosomes and
FT tethering to chromatin, leading to strong constitutive
FT activation in the absence of DNA."
FT /evidence="ECO:0000269|PubMed:31808743,
FT ECO:0000269|PubMed:32911480, ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:32911482, ECO:0000269|PubMed:32912999,
FT ECO:0000269|PubMed:33051594"
FT MUTAGEN 258
FT /note="K->A: Slightly decreased interaction with histones
FT H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594"
FT MUTAGEN 258
FT /note="K->E: Does not affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 275
FT /note="K->E: Reduced nucleotidyltransferase activity.
FT Abolished nucleotidyltransferase activity; when associated
FT with E-285."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 279..282
FT /note="KFRK->EFRE: Strongly reduced nucleotidyltransferase
FT activity."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 279
FT /note="K->E: Reduced nucleotidyltransferase activity."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 285
FT /note="K->E: Strongly reduced nucleotidyltransferase
FT activity. Abolished nucleotidyltransferase activity; when
FT associated with E-275."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 295..305
FT /note="Missing: Abolished nuclear localization."
FT /evidence="ECO:0000269|PubMed:30356214"
FT MUTAGEN 300..301
FT /note="RK->EE,AA: Abolished nucleotidyltransferase
FT activity."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 300
FT /note="R->E: Reduced nucleotidyltransferase activity."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 305
FT /note="S->A: Enhanced stimulation of interferon production.
FT Does not affect chromosome localization."
FT /evidence="ECO:0000269|PubMed:26440888,
FT ECO:0000269|PubMed:32351706"
FT MUTAGEN 305
FT /note="S->D: Phospho-mimetic mutant; decreased ability to
FT trigger type-I interferon production."
FT /evidence="ECO:0000269|PubMed:32351706"
FT MUTAGEN 319
FT /note="D->A: Abolishes enzyme activity. Does not affect
FT translocation to the nucleus following treatment with
FT etoposide. Abolished cleavage by CASP3."
FT /evidence="ECO:0000269|PubMed:30356214,
FT ECO:0000269|PubMed:30878284"
FT MUTAGEN 327
FT /note="K->A: Slightly decreased interaction with histones
FT H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594"
FT MUTAGEN 327
FT /note="K->E: Abolishes stimulation of interferon
FT production; when associated with E-236 and E-254. Does not
FT affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:32911481"
FT MUTAGEN 328
FT /note="S->A: Slightly decreased interaction with histones
FT H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594"
FT MUTAGEN 329
FT /note="S->A: Decreased interaction with histones H2A and
FT H2B."
FT /evidence="ECO:0000269|PubMed:33051594"
FT MUTAGEN 347
FT /note="K->A,E: Impaired association with collided ribosomes
FT in response to translation stress. Abolishes stimulation of
FT interferon production. Decreased interaction with
FT nucleosomes."
FT /evidence="ECO:0000269|PubMed:24462292,
FT ECO:0000269|PubMed:32911481, ECO:0000269|PubMed:34111399"
FT MUTAGEN 349
FT /note="R->A: Impaired association with collided ribosomes
FT in response to translation stress. Decreased interaction
FT with histones H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594,
FT ECO:0000269|PubMed:34111399"
FT MUTAGEN 349
FT /note="R->E: Impaired association with collided ribosomes
FT in response to translation stress. Decreased interaction
FT with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:34111399"
FT MUTAGEN 350
FT /note="K->A: Impaired association with collided ribosomes
FT in response to translation stress. Does not affect
FT interaction with histones H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594,
FT ECO:0000269|PubMed:34111399"
FT MUTAGEN 350
FT /note="K->E: Impaired association with collided ribosomes
FT in response to translation stress. Decreased interaction
FT with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481,
FT ECO:0000269|PubMed:34111399"
FT MUTAGEN 353
FT /note="R->A,E: Impaired association with collided ribosomes
FT in response to translation stress. Strongly decreased
FT interaction with histones H2A and H2B."
FT /evidence="ECO:0000269|PubMed:33051594,
FT ECO:0000269|PubMed:34111399"
FT MUTAGEN 353
FT /note="R->E: Abolishes stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:24462292"
FT MUTAGEN 355
FT /note="K->E: Does not affect interaction with nucleosomes."
FT /evidence="ECO:0000269|PubMed:32911481"
FT MUTAGEN 376
FT /note="R->I: Alters enzyme activity, leading to the
FT appearance of 3'-5' linked cGAMP. Abolishes enzyme
FT activity; when associated with Q-211 and I-436."
FT /evidence="ECO:0000269|PubMed:25131990"
FT MUTAGEN 384
FT /note="K->A,E: Abolishes stimulation of interferon
FT production. Abolishes DNA-binding but does not affect
FT translocation to the nucleus following treatment with
FT etoposide; when associated with 210-A--A-214."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:24116191, ECO:0000269|PubMed:30356214"
FT MUTAGEN 384
FT /note="K->Q: Acetylation-mimetic mutant; reduced enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 384
FT /note="K->R: No effect on stimulation of interferon
FT production. Strongly decreased ubiquitination by RNF185;
FT when associated with R-173."
FT /evidence="ECO:0000269|PubMed:28273161,
FT ECO:0000269|PubMed:30799039"
FT MUTAGEN 390
FT /note="H->A: Strongly reduces stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23707061"
FT MUTAGEN 392
FT /note="K->Q: Acetylation-mimetic mutant; no effect."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 392
FT /note="K->R: No effect."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 394
FT /note="K->A: Abolishes enzyme activity. No effect on
FT stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:24462292"
FT MUTAGEN 394
FT /note="K->E: Abolishes homodimerization and subsequent
FT nucleotidyltransferase activity. Abolishes stimulation of
FT interferon production. Does not affect subcellular location
FT to the nucleus and cytosol."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:31544964, ECO:0000269|PubMed:32911482"
FT MUTAGEN 394
FT /note="K->Q: Acetylation-mimetic mutant; reduced enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 394
FT /note="K->R: No effect on stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 396..397
FT /note="CC->AA: Abolishes DNA binding and enzyme activity.
FT Abolishes stimulation of interferon production. Decreased
FT localization to the nucleus."
FT /evidence="ECO:0000269|PubMed:23722159,
FT ECO:0000269|PubMed:30827685, ECO:0000269|PubMed:31544964"
FT MUTAGEN 396
FT /note="C->A: Abolishes DNA binding and enzyme activity."
FT /evidence="ECO:0000269|PubMed:23707061"
FT MUTAGEN 397
FT /note="C->A: Abolishes stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23707061"
FT MUTAGEN 400
FT /note="K->E: Abolishes stimulation of interferon
FT production; when associated with E-403."
FT /evidence="ECO:0000269|PubMed:24116191"
FT MUTAGEN 403
FT /note="K->E: Abolishes stimulation of interferon
FT production; when associated with E-400."
FT /evidence="ECO:0000269|PubMed:24116191"
FT MUTAGEN 404
FT /note="C->A: Abolishes stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23707061"
FT MUTAGEN 407..411
FT /note="KDCLK->EDCLA: Prevents activation in response to
FT DNA-binding; leading to abolished enzyme activity and
FT stimulation of interferon production."
FT /evidence="ECO:0000269|PubMed:23722159,
FT ECO:0000269|PubMed:31299200"
FT MUTAGEN 407
FT /note="K->A: Abolishes enzyme activity. Abolishes
FT stimulation of interferon production. Abolishes DNA-binding
FT but does not affect translocation to the nucleus following
FT treatment with etoposide; when associated with 171-K--L-174
FT Del."
FT /evidence="ECO:0000269|PubMed:23707061,
FT ECO:0000269|PubMed:30356214"
FT MUTAGEN 414
FT /note="K->A,E: Abolishes stimulation of interferon
FT production."
FT /evidence="ECO:0000269|PubMed:23707061"
FT MUTAGEN 414
FT /note="K->Q: Acetylation-mimetic mutant; reduced enzyme
FT activity."
FT /evidence="ECO:0000269|PubMed:30799039"
FT MUTAGEN 414
FT /note="K->R: Reduced enzyme activity. Decreased
FT ubiquitination and SQSTM1-mediated autophagic degradation."
FT /evidence="ECO:0000269|PubMed:27666593,
FT ECO:0000269|PubMed:30799039"
FT MUTAGEN 427..428
FT /note="KK->AA: Reduced nucleotidyltransferase activity."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 427..428
FT /note="KK->EE: Abolished nucleotidyltransferase activity."
FT /evidence="ECO:0000269|PubMed:31142647"
FT MUTAGEN 434
FT /note="S->C: Gains susceptibility to mouse-specific RU.521;
FT when associated with H-482."
FT /evidence="ECO:0000269|PubMed:30007416"
FT MUTAGEN 435
FT /note="S->A: Decreased cyclic GMP-AMP synthase activity."
FT /evidence="ECO:0000269|PubMed:32474700"
FT MUTAGEN 435
FT /note="S->D: Phospho-mimetic mutant; increased cyclic GMP-
FT AMP synthase activity."
FT /evidence="ECO:0000269|PubMed:32474700"
FT MUTAGEN 436
FT /note="Y->I: Abolishes enzyme activity; when associated
FT with Q-211 and I-376."
FT /evidence="ECO:0000269|PubMed:25131990"
FT MUTAGEN 479
FT /note="K->R: Reduced sumoylation."
FT /evidence="ECO:0000269|PubMed:27637147"
FT MUTAGEN 482
FT /note="N->H: Gains susceptibility to mouse-specific RU.521;
FT when associated with C-434."
FT /evidence="ECO:0000269|PubMed:30007416"
FT STRAND 157..159
FT /evidence="ECO:0007829|PDB:4LEV"
FT HELIX 162..173
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 176..198
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 201..203
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 206..208
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 210..212
FT /evidence="ECO:0007829|PDB:6O47"
FT HELIX 213..216
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 220..222
FT /evidence="ECO:0007829|PDB:4O67"
FT STRAND 225..233
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 235..242
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 246..253
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 257..259
FT /evidence="ECO:0007829|PDB:6MJX"
FT HELIX 261..265
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 266..271
FT /evidence="ECO:0007829|PDB:6LRI"
FT HELIX 273..288
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 294..298
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 304..306
FT /evidence="ECO:0007829|PDB:4LEV"
FT STRAND 308..312
FT /evidence="ECO:0007829|PDB:6LRC"
FT TURN 313..315
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 316..326
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 332..334
FT /evidence="ECO:0007829|PDB:6LRC"
FT TURN 341..344
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 346..353
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 357..361
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 364..369
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 370..373
FT /evidence="ECO:0007829|PDB:5VDU"
FT STRAND 375..378
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 380..388
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 391..393
FT /evidence="ECO:0007829|PDB:4LEW"
FT TURN 394..397
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 400..402
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 406..423
FT /evidence="ECO:0007829|PDB:6LRC"
FT STRAND 425..428
FT /evidence="ECO:0007829|PDB:6LRC"
FT TURN 429..432
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 435..448
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 452..455
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 457..459
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 460..477
FT /evidence="ECO:0007829|PDB:6LRC"
FT TURN 493..495
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 498..513
FT /evidence="ECO:0007829|PDB:6LRC"
FT HELIX 517..519
FT /evidence="ECO:0007829|PDB:6LRC"
SQ SEQUENCE 522 AA; 58814 MW; 808FF6F9F3BF8C50 CRC64;
MQPWHGKAMQ RASEAGATAP KASARNARGA PMDPTESPAA PEAALPKAGK FGPARKSGSR
QKKSAPDTQE RPPVRATGAR AKKAPQRAQD TQPSDATSAP GAEGLEPPAA REPALSRAGS
CRQRGARCST KPRPPPGPWD VPSPGLPVSA PILVRRDAAP GASKLRAVLE KLKLSRDDIS
TAAGMVKGVV DHLLLRLKCD SAFRGVGLLN TGSYYEHVKI SAPNEFDVMF KLEVPRIQLE
EYSNTRAYYF VKFKRNPKEN PLSQFLEGEI LSASKMLSKF RKIIKEEIND IKDTDVIMKR
KRGGSPAVTL LISEKISVDI TLALESKSSW PASTQEGLRI QNWLSAKVRK QLRLKPFYLV
PKHAKEGNGF QEETWRLSFS HIEKEILNNH GKSKTCCENK EEKCCRKDCL KLMKYLLEQL
KERFKDKKHL DKFSSYHVKT AFFHVCTQNP QDSQWDRKDL GLCFDNCVTY FLQCLRTEKL
ENYFIPEFNL FSSNLIDKRS KEFLTKQIEY ERNNEFPVFD EF
