CARD8_HUMAN
ID CARD8_HUMAN Reviewed; 537 AA.
AC Q9Y2G2; B5KVR6; B5KVR8; B7Z496; B7Z4A2; E5RFV9; E9PEM7; G3XAM9; Q6PGP8;
AC Q96P82;
DT 20-JUN-2001, integrated into UniProtKB/Swiss-Prot.
DT 02-JUN-2021, sequence version 2.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=Caspase recruitment domain-containing protein 8 {ECO:0000305};
DE EC=3.4.-.- {ECO:0000269|PubMed:22087307};
DE AltName: Full=CARD-inhibitor of NF-kappa-B-activating ligand {ECO:0000303|PubMed:11551959};
DE Short=CARDINAL {ECO:0000303|PubMed:11551959};
DE AltName: Full=Tumor up-regulated CARD-containing antagonist of CASP9 {ECO:0000303|PubMed:18212821};
DE Short=TUCAN {ECO:0000303|PubMed:18212821};
DE Contains:
DE RecName: Full=Caspase recruitment domain-containing protein 8, C-terminus {ECO:0000305};
DE Short=CARD8-CT {ECO:0000303|PubMed:33420033};
DE Contains:
DE RecName: Full=Caspase recruitment domain-containing protein 8, N-terminus {ECO:0000305};
DE Short=CARD8-NT {ECO:0000303|PubMed:33420033};
GN Name=CARD8 {ECO:0000303|PubMed:11821383, ECO:0000312|HGNC:HGNC:17057};
GN Synonyms=DACAR {ECO:0000303|Ref.4}, KIAA0955 {ECO:0000303|PubMed:10231032},
GN NDPP1 {ECO:0000303|PubMed:11956601};
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 [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=10231032; DOI=10.1093/dnares/6.1.63;
RA Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N.,
RA Tanaka A., Kotani H., Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. XIII. The
RT complete sequences of 100 new cDNA clones from brain which code for large
RT proteins in vitro.";
RL DNA Res. 6:63-70(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, TISSUE SPECIFICITY, AND
RP INTERACTION WITH CARD16 AND CARD18.
RX PubMed=11821383; DOI=10.1074/jbc.m107811200;
RA Razmara M., Srinivasula S.M., Wang L., Poyet J.-L., Geddes B.J.,
RA DiStefano P.S., Bertin J., Alnemri E.S.;
RT "CARD-8 protein, a new CARD family member that regulates caspase-1
RT activation and apoptosis.";
RL J. Biol. Chem. 277:13952-13958(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=11956601;
RA Zhang H., Fu W.;
RT "NDPP1 is a novel CARD domain containing protein which can inhibit
RT apoptosis and suppress NF-kappaB activation.";
RL Int. J. Oncol. 20:1035-1040(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Guiet C., Vito P.;
RT "DACAR, a novel CARD-containing protein.";
RL Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, INTERACTION WITH IKBKG,
RP AND TISSUE SPECIFICITY.
RX PubMed=11551959; DOI=10.1074/jbc.m107373200;
RA Bouchier-Hayes L., Conroy H., Egan H., Adrain C., Creagh E.M.,
RA MacFarlane M., Martin S.J.;
RT "CARDINAL, a novel caspase recruitment domain protein, is an inhibitor of
RT multiple NF-kappa B activation pathways.";
RL J. Biol. Chem. 276:44069-44077(2001).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 5 AND 7), AND ALTERNATIVE SPLICING.
RX PubMed=18212821; DOI=10.1038/sj.ejhg.5201996;
RA Bagnall R.D., Roberts R.G., Mirza M.M., Torigoe T., Prescott N.J.,
RA Mathew C.G.;
RT "Novel isoforms of the CARD8 (TUCAN) gene evade a nonsense mutation.";
RL Eur. J. Hum. Genet. 16:619-625(2008).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Kidney;
RA Guo J.H., Yu L.;
RL Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 3 AND 4), AND VARIANTS
RP VAL-173 AND ALA-204.
RC TISSUE=Umbilical cord blood;
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15057824; DOI=10.1038/nature02399;
RA Grimwood J., Gordon L.A., Olsen A.S., Terry A., Schmutz J., Lamerdin J.E.,
RA Hellsten U., Goodstein D., Couronne O., Tran-Gyamfi M., Aerts A.,
RA Altherr M., Ashworth L., Bajorek E., Black S., Branscomb E., Caenepeel S.,
RA Carrano A.V., Caoile C., Chan Y.M., Christensen M., Cleland C.A.,
RA Copeland A., Dalin E., Dehal P., Denys M., Detter J.C., Escobar J.,
RA Flowers D., Fotopulos D., Garcia C., Georgescu A.M., Glavina T., Gomez M.,
RA Gonzales E., Groza M., Hammon N., Hawkins T., Haydu L., Ho I., Huang W.,
RA Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Larionov V.,
RA Leem S.-H., Lopez F., Lou Y., Lowry S., Malfatti S., Martinez D.,
RA McCready P.M., Medina C., Morgan J., Nelson K., Nolan M., Ovcharenko I.,
RA Pitluck S., Pollard M., Popkie A.P., Predki P., Quan G., Ramirez L.,
RA Rash S., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A.,
RA She X., Smith D., Slezak T., Solovyev V., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wagner M., Wheeler J., Wu K., Xie G., Yang J.,
RA Dubchak I., Furey T.S., DeJong P., Dickson M., Gordon D., Eichler E.E.,
RA Pennacchio L.A., Richardson P., Stubbs L., Rokhsar D.S., Myers R.M.,
RA Rubin E.M., Lucas S.M.;
RT "The DNA sequence and biology of human chromosome 19.";
RL Nature 428:529-535(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Eye;
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 [12]
RP PROTEIN SEQUENCE OF 284-304, FUNCTION, AUTOCATALYTIC CLEAVAGE, AND
RP MUTAGENESIS OF GLU-240; GLU-242; HIS-252; HIS-270; GLU-279; HIS-280;
RP SER-295; PHE-296; SER-297 AND HIS-333.
RX PubMed=22087307; DOI=10.1371/journal.pone.0027396;
RA D'Osualdo A., Weichenberger C.X., Wagner R.N., Godzik A., Wooley J.,
RA Reed J.C.;
RT "CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like
RT domain.";
RL PLoS ONE 6:E27396-E27396(2011).
RN [13]
RP FUNCTION.
RX PubMed=11408476; DOI=10.1074/jbc.m100433200;
RA Pathan N., Marusawa H., Krajewska M., Matsuzawa S., Kim H., Okada K.,
RA Torii S., Kitada S., Krajewski S., Welsh K., Pio F., Godzik A., Reed J.C.;
RT "TUCAN, an antiapoptotic caspase-associated recruitment domain family
RT protein overexpressed in cancer.";
RL J. Biol. Chem. 276:32220-32229(2001).
RN [14]
RP FUNCTION, INTERACTION WITH DRAL, AND MUTAGENESIS OF LEU-472.
RX PubMed=12067710; DOI=10.1016/s0014-5793(02)02869-7;
RA Stilo R., Leonardi A., Formisano L., Di Jeso B., Vito P., Liguoro D.;
RT "TUCAN/CARDINAL and DRAL participate in a common pathway for modulation of
RT NF-kappaB activation.";
RL FEBS Lett. 521:165-169(2002).
RN [15]
RP FUNCTION, INTERACTION WITH NLRP2, AND SUBCELLULAR LOCATION.
RX PubMed=15030775; DOI=10.1016/s1074-7613(04)00046-9;
RA Agostini L., Martinon F., Burns K., McDermott M.F., Hawkins P.N.,
RA Tschopp J.;
RT "NALP3 forms an IL-1beta-processing inflammasome with increased activity in
RT Muckle-Wells autoinflammatory disorder.";
RL Immunity 20:319-325(2004).
RN [16]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NLRP3.
RX PubMed=24517500; DOI=10.1186/ar4483;
RA Ito S., Hara Y., Kubota T.;
RT "CARD8 is a negative regulator for NLRP3 inflammasome, but mutant NLRP3 in
RT cryopyrin-associated periodic syndromes escapes the restriction.";
RL Arthritis Res. Ther. 16:R52-R52(2014).
RN [17]
RP ACTIVITY REGULATION, AND MUTAGENESIS OF SER-297.
RX PubMed=29967349; DOI=10.1038/s41591-018-0082-y;
RA Johnson D.C., Taabazuing C.Y., Okondo M.C., Chui A.J., Rao S.D.,
RA Brown F.C., Reed C., Peguero E., de Stanchina E., Kentsis A.,
RA Bachovchin D.A.;
RT "DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid
RT leukemia.";
RL Nat. Med. 24:1151-1156(2018).
RN [18]
RP INTERACTION WITH DPP8 AND DPP9, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP SER-297.
RX PubMed=31525884; DOI=10.1021/acschembio.9b00462;
RA Griswold A.R., Ball D.P., Bhattacharjee A., Chui A.J., Rao S.D.,
RA Taabazuing C.Y., Bachovchin D.A.;
RT "DPP9's enzymatic activity and not its binding to CARD8 inhibits
RT inflammasome activation.";
RL ACS Chem. Biol. 14:2424-2429(2019).
RN [19]
RP ACTIVITY REGULATION.
RX PubMed=32796818; DOI=10.1038/s41419-020-02865-4;
RA Johnson D.C., Okondo M.C., Orth E.L., Rao S.D., Huang H.C., Ball D.P.,
RA Bachovchin D.A.;
RT "DPP8/9 inhibitors activate the CARD8 inflammasome in resting
RT lymphocytes.";
RL Cell Death Dis. 11:628-628(2020).
RN [20]
RP FUNCTION, ACTIVITY REGULATION, DOMAIN, UBIQUITINATION, MUTAGENESIS OF
RP GLN-152 (ISOFORM 1), AND MUTAGENESIS OF LYS-157.
RX PubMed=33053349; DOI=10.1016/j.celrep.2020.108264;
RA Chui A.J., Griswold A.R., Taabazuing C.Y., Orth E.L., Gai K., Rao S.D.,
RA Ball D.P., Hsiao J.C., Bachovchin D.A.;
RT "Activation of the CARD8 inflammasome requires a disordered region.";
RL Cell Rep. 33:108264-108264(2020).
RN [21]
RP FUNCTION, ACTIVITY REGULATION, AND SUBCELLULAR LOCATION.
RX PubMed=32840892; DOI=10.15252/embj.2020105071;
RA Linder A., Bauernfried S., Cheng Y., Albanese M., Jung C., Keppler O.T.,
RA Hornung V.;
RT "CARD8 inflammasome activation triggers pyroptosis in human T cells.";
RL EMBO J. 39:e105071-e105071(2020).
RN [22]
RP REVIEW.
RX PubMed=32558991; DOI=10.1111/imr.12884;
RA Taabazuing C.Y., Griswold A.R., Bachovchin D.A.;
RT "The NLRP1 and CARD8 inflammasomes.";
RL Immunol. Rev. 297:13-25(2020).
RN [23]
RP FUNCTION, SUBUNIT, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF SER-297.
RX PubMed=32051255; DOI=10.26508/lsa.202000664;
RA Ball D.P., Taabazuing C.Y., Griswold A.R., Orth E.L., Rao S.D.,
RA Kotliar I.B., Vostal L.E., Johnson D.C., Bachovchin D.A.;
RT "Caspase-1 interdomain linker cleavage is required for pyroptosis.";
RL Life. Sci Alliance 3:0-0(2020).
RN [24]
RP SUBCELLULAR LOCATION.
RX PubMed=33154409; DOI=10.1038/s41598-020-73600-4;
RA Paramel G.V., Karadimou G., Eremo A.G., Ljungberg L.U., Hedin U.,
RA Olofsson P.S., Folkersen L., Berne G.P., Sirsjoe A., Fransen K.;
RT "Expression of CARD8 in human atherosclerosis and its regulation of
RT inflammatory proteins in human endothelial cells.";
RL Sci. Rep. 10:19108-19108(2020).
RN [25]
RP INTERACTION WITH DPP9.
RX PubMed=33731929; DOI=10.1038/s41586-021-03320-w;
RA Huang M., Zhang X., Toh G.A., Gong Q., Wang J., Han Z., Wu B., Zhong F.,
RA Chai J.;
RT "Structural and biochemical mechanisms of NLRP1 inhibition by DPP9.";
RL Nature 592:773-777(2021).
RN [26]
RP FUNCTION, SUBUNIT, ACTIVITY REGULATION, PROTEOLYTIC CLEAVAGE (MICROBIAL
RP INFECTION), SUBCELLULAR LOCATION, AND MUTAGENESIS OF LEU-51; GLN-52;
RP TYR-53; THR-54; LYS-55; THR-56; GLY-57; ILE-58; PHE-59; PHE-60 AND SER-297.
RX PubMed=33542150; DOI=10.1126/science.abe1707;
RA Wang Q., Gao H., Clark K.M., Mugisha C.S., Davis K., Tang J.P.,
RA Harlan G.H., DeSelm C.J., Presti R.M., Kutluay S.B., Shan L.;
RT "CARD8 is an inflammasome sensor for HIV-1 protease activity.";
RL Science 0:0-0(2021).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (2.46 ANGSTROMS) OF 451-537.
RX PubMed=23695559; DOI=10.1107/s1744309113010075;
RA Jin T., Huang M., Smith P., Jiang J., Xiao T.S.;
RT "The structure of the CARD8 caspase-recruitment domain suggests its
RT association with the FIIND domain and procaspases through adjacent
RT surfaces.";
RL Acta Crystallogr. F 69:482-487(2013).
RN [28] {ECO:0007744|PDB:7JKQ, ECO:0007744|PDB:7JN7}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.30 ANGSTROMS) IN COMPLEX WITH DPP9,
RP FUNCTION, ACTIVITY REGULATION, INTERACTION WITH DPP9, AND MUTAGENESIS OF
RP GLU-274; SER-297; LEU-368; PHE-370; ARG-394 AND PHE-405.
RX PubMed=34019797; DOI=10.1016/j.immuni.2021.04.024;
RA Sharif H., Hollingsworth L.R., Griswold A.R., Hsiao J.C., Wang Q.,
RA Bachovchin D.A., Wu H.;
RT "Dipeptidyl peptidase 9 sets a threshold for CARD8 inflammasome formation
RT by sequestering its active C-terminal fragment.";
RL Immunity 54:1392-1404(2021).
RN [29] {ECO:0007744|PDB:6K9F}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.70 ANGSTROMS) OF 451-537, SUBCELLULAR
RP LOCATION, SUBUNIT, AND DOMAIN.
RX PubMed=33420028; DOI=10.1038/s41467-020-20319-5;
RA Gong Q., Robinson K., Xu C., Huynh P.T., Chong K.H.C., Tan E.Y.J.,
RA Zhang J., Boo Z.Z., Teo D.E.T., Lay K., Zhang Y., Lim J.S.Y., Goh W.I.,
RA Wright G., Zhong F.L., Reversade B., Wu B.;
RT "Structural basis for distinct inflammasome complex assembly by human NLRP1
RT and CARD8.";
RL Nat. Commun. 12:188-188(2021).
RN [30] {ECO:0007744|PDB:6XKJ}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.54 ANGSTROMS) OF 451-537, SUBCELLULAR
RP LOCATION, SUBUNIT, DOMAIN, AND MUTAGENESIS OF ARG-459; ARG-464; GLU-485;
RP GLU-490; ARG-495; ASP-511 AND TYR-527.
RX PubMed=33420033; DOI=10.1038/s41467-020-20320-y;
RA Robert Hollingsworth L., David L., Li Y., Griswold A.R., Ruan J.,
RA Sharif H., Fontana P., Orth-He E.L., Fu T.M., Bachovchin D.A., Wu H.;
RT "Mechanism of filament formation in UPA-promoted CARD8 and NLRP1
RT inflammasomes.";
RL Nat. Commun. 12:189-189(2021).
RN [31]
RP VARIANT IBD30 10-CYS--LEU-431 DEL (ISOFORM 1), AND VARIANT IBD30 ILE-102.
RX PubMed=17030188; DOI=10.1053/j.gastro.2006.08.008;
RA McGovern D.P., Butler H., Ahmad T., Paolucci M., van Heel D.A., Negoro K.,
RA Hysi P., Ragoussis J., Travis S.P., Cardon L.R., Jewell D.P.;
RT "TUCAN (CARD8) genetic variants and inflammatory bowel disease.";
RL Gastroenterology 131:1190-1196(2006).
RN [32]
RP VARIANT IBD30 10-CYS--LEU-431 DEL (ISOFORM 1), AND VARIANT IBD30 ILE-102.
RX PubMed=19319132; DOI=10.1038/ajg.2009.29;
RA Schoultz I., Verma D., Halfvarsson J., Toerkvist L., Fredrikson M.,
RA Sjoeqvist U., Loerdal M., Tysk C., Lerm M., Soederkvist P.,
RA Soederholm J.D.;
RT "Combined polymorphisms in genes encoding the inflammasome components NALP3
RT and CARD8 confer susceptibility to Crohn's disease in Swedish men.";
RL Am. J. Gastroenterol. 104:1180-1188(2009).
RN [33]
RP VARIANT IBD30 10-CYS--LEU-431 DEL (ISOFORM 1), AND VARIANT IBD30 ILE-102.
RX PubMed=23506543; DOI=10.1186/1471-2350-14-35;
RA Vasseur F., Sendid B., Broly F., Gower-Rousseau C., Sarazin A.,
RA Standaert-Vitse A., Colombel J.F., Poulain D., Jouault T.;
RT "The CARD8 p.C10X mutation associates with a low anti-glycans antibody
RT response in patients with Crohn's disease.";
RL BMC Med. Genet. 14:35-35(2013).
RN [34]
RP VARIANT IBD30 10-CYS--LEU-431 DEL (ISOFORM 1), AND VARIANT IBD30 ILE-102.
RX PubMed=26462578; DOI=10.3109/08916934.2015.1045581;
RA Zhang Z.T., Ma X.J., Zong Y., Du X.M., Hu J.H., Lu G.C.;
RT "Is the CARD8 rs2043211 polymorphism associated with susceptibility to
RT Crohn's disease? A meta-analysis.";
RL Autoimmunity 48:524-531(2015).
RN [35]
RP VARIANT IBD30 ILE-44.
RX PubMed=29408806; DOI=10.1172/jci98642;
RA Mao L., Kitani A., Similuk M., Oler A.J., Albenberg L., Kelsen J.,
RA Aktay A., Quezado M., Yao M., Montgomery-Recht K., Fuss I.J., Strober W.;
RT "Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and
RT Crohn's disease.";
RL J. Clin. Invest. 128:1793-1806(2018).
CC -!- FUNCTION: Inflammasome sensor, which mediates inflammasome activation
CC in response to various pathogen-associated signals, leading to
CC subsequent pyroptosis of CD4(+) T-cells and macrophages
CC (PubMed:11821383, PubMed:11408476, PubMed:15030775, PubMed:32840892,
CC PubMed:32051255, PubMed:33542150, PubMed:34019797). Inflammasomes are
CC supramolecular complexes that assemble in the cytosol in response to
CC pathogens and other damage-associated signals and play critical roles
CC in innate immunity and inflammation (PubMed:11821383, PubMed:11408476,
CC PubMed:15030775). Acts as a recognition receptor (PRR): recognizes
CC specific pathogens and other damage-associated signals, such as HIV-1
CC protease activity or Val-boroPro inhibitor, and mediates CARD8
CC inflammasome activation (PubMed:32840892, PubMed:33542150). In response
CC to pathogen-associated signals, the N-terminal part of CARD8 is
CC degraded by the proteasome, releasing the cleaved C-terminal part of
CC the protein (Caspase recruitment domain-containing protein 8, C-
CC terminus), which polymerizes to initiate the formation of the
CC inflammasome complex: the CARD8 inflammasome directly recruits pro-
CC caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1
CC (CASP1) activation, which subsequently cleaves and activates
CC inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading
CC to pyroptosis (PubMed:33053349, PubMed:32840892, PubMed:32051255,
CC PubMed:33542150). Ability to sense HIV-1 protease activity leads to the
CC clearance of latent HIV-1 in patient CD4(+) T-cells after viral
CC reactivation; in contrast, HIV-1 can evade CARD8-sensing when its
CC protease remains inactive in infected cells prior to viral budding
CC (PubMed:33542150). Also acts as a negative regulator of the NLRP3
CC inflammasome (PubMed:24517500). May also act as an inhibitor of NF-
CC kappa-B activation (PubMed:11551959, PubMed:12067710).
CC {ECO:0000269|PubMed:11408476, ECO:0000269|PubMed:11551959,
CC ECO:0000269|PubMed:11821383, ECO:0000269|PubMed:12067710,
CC ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:24517500,
CC ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:32840892,
CC ECO:0000269|PubMed:33053349, ECO:0000269|PubMed:33542150,
CC ECO:0000269|PubMed:34019797}.
CC -!- FUNCTION: [Caspase recruitment domain-containing protein 8]:
CC Constitutes the precursor of the CARD8 inflammasome, which mediates
CC autoproteolytic processing within the FIIND domain to generate the N-
CC terminal and C-terminal parts, which are associated non-covalently in
CC absence of pathogens and other damage-associated signals.
CC {ECO:0000269|PubMed:22087307}.
CC -!- FUNCTION: [Caspase recruitment domain-containing protein 8, N-
CC terminus]: Regulatory part that prevents formation of the CARD8
CC inflammasome: in absence of pathogens and other damage-associated
CC signals, interacts with the C-terminal part of CARD8 (Caspase
CC recruitment domain-containing protein 8, C-terminus), preventing
CC activation of the CARD8 inflammasome (PubMed:33542150). In response to
CC pathogen-associated signals, this part is ubiquitinated by the N-end
CC rule pathway and degraded by the proteasome, releasing the cleaved C-
CC terminal part of the protein, which polymerizes and forms the CARD8
CC inflammasome (Probable) (PubMed:32558991).
CC {ECO:0000269|PubMed:33542150, ECO:0000303|PubMed:32558991,
CC ECO:0000305|PubMed:33053349}.
CC -!- FUNCTION: [Caspase recruitment domain-containing protein 8, C-
CC terminus]: Constitutes the active part of the CARD8 inflammasome
CC (PubMed:32840892, PubMed:34019797). In absence of pathogens and other
CC damage-associated signals, interacts with the N-terminal part of CARD8
CC (Caspase recruitment domain-containing protein 8, N-terminus),
CC preventing activation of the CARD8 inflammasome (PubMed:33542150). In
CC response to pathogen-associated signals, the N-terminal part of CARD8
CC is degraded by the proteasome, releasing this form, which polymerizes
CC to form the CARD8 inflammasome complex: the CARD8 inflammasome complex
CC then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1
CC (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and
CC subsequent pyroptosis (PubMed:32840892, PubMed:33542150).
CC {ECO:0000269|PubMed:32840892, ECO:0000269|PubMed:33542150,
CC ECO:0000269|PubMed:34019797}.
CC -!- ACTIVITY REGULATION: CARD8 inflammasome is activated by HIV-1 protease
CC activity: HIV-1 protease cleaves CARD8, promoting ubiquitination and
CC degradation of the N-terminal part, releasing the cleaved C-terminal
CC part of the protein (Caspase recruitment domain-containing protein 8,
CC C-terminus), which polymerizes and forms the CARD8 inflammasome
CC (PubMed:33542150). CARD8 inflammasome is inhibited by DPP8 and DPP9,
CC which sequester the C-terminal fragment of CARD8 (Caspase recruitment
CC domain-containing protein 8, C-terminus) in a ternary complex, thereby
CC preventing CARD8 oligomerization and activation (PubMed:29967349,
CC PubMed:31525884, PubMed:32796818, PubMed:34019797). CARD8 inflammasome
CC is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of
CC dipeptidyl peptidases DPP8 and DPP9 (PubMed:29967349, PubMed:31525884,
CC PubMed:32796818, PubMed:33053349, PubMed:32840892, PubMed:34019797).
CC Val-boroPro relieves inhibition of DPP8 and/or DPP9 by inducing the
CC proteasome-mediated destruction of the N-terminal part of CARD8,
CC releasing its C-terminal part from autoinhibition (PubMed:29967349,
CC PubMed:31525884, PubMed:32796818, PubMed:34019797).
CC {ECO:0000269|PubMed:29967349, ECO:0000269|PubMed:31525884,
CC ECO:0000269|PubMed:32796818, ECO:0000269|PubMed:32840892,
CC ECO:0000269|PubMed:33053349, ECO:0000269|PubMed:33542150,
CC ECO:0000269|PubMed:34019797}.
CC -!- SUBUNIT: Interacts with DPP9; leading to inhibit activation of the
CC inflammasome (PubMed:31525884, PubMed:33731929, PubMed:34019797). DPP9
CC acts via formation of a ternary complex, composed of a DPP9 homodimer,
CC one full-length CARD8 protein, and one cleaved C-terminus of CARD8
CC (Caspase recruitment domain-containing protein 8, C-terminus)
CC (PubMed:34019797). Interacts with DPP8; leading to inhibit activation
CC of the inflammasome, probably via formation of a ternary complex with
CC DPP8 (PubMed:31525884). Interacts with NLRP3 (PubMed:24517500).
CC Interacts with IKBKG/NEMO (PubMed:11551959). Interacts with DRAL
CC (PubMed:12067710). Binds to caspase-1 (CASP1), CARD16/pseudo-ICE and
CC CARD18/ICEBERG (PubMed:11821383). Interacts with NLRP2 (via NACHT
CC domain) (PubMed:15030775). {ECO:0000269|PubMed:11551959,
CC ECO:0000269|PubMed:11821383, ECO:0000269|PubMed:12067710,
CC ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:24517500,
CC ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:33731929,
CC ECO:0000269|PubMed:34019797}.
CC -!- SUBUNIT: [Caspase recruitment domain-containing protein 8, N-terminus]:
CC Interacts with the C-terminal part of CARD8 (Caspase recruitment
CC domain-containing protein 8, C-terminus) in absence of pathogens and
CC other damage-associated signals. {ECO:0000269|PubMed:33542150}.
CC -!- SUBUNIT: [Caspase recruitment domain-containing protein 8, C-terminus]:
CC Interacts with the N-terminal part of CARD8 (Caspase recruitment
CC domain-containing protein 8, N-terminus) in absence of pathogens and
CC other damage-associated signals (PubMed:33542150). Homomultimer; forms
CC the CARD8 inflammasome polymeric complex, a filament composed of
CC homopolymers of this form in response to pathogens and other damage-
CC associated signals (PubMed:33420028, PubMed:33420033). The CARD8
CC inflammasome polymeric complex directly recruits pro-caspase-1
CC (proCASP1) independently of PYCARD/ASC (PubMed:32051255). Interacts
CC (via CARD domain) with CASP1 (via CARD domain); leading to CASP1
CC activation (PubMed:33542150, PubMed:33420033).
CC {ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:33420028,
CC ECO:0000269|PubMed:33420033, ECO:0000269|PubMed:33542150}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15030775,
CC ECO:0000269|PubMed:24517500, ECO:0000269|PubMed:33154409}. Nucleus
CC {ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:33154409}.
CC -!- SUBCELLULAR LOCATION: [Caspase recruitment domain-containing protein 8,
CC C-terminus]: Inflammasome {ECO:0000269|PubMed:32840892,
CC ECO:0000269|PubMed:33420028, ECO:0000269|PubMed:33420033,
CC ECO:0000269|PubMed:33542150}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=5; Synonyms=T60 {ECO:0000303|PubMed:18212821}, a;
CC IsoId=Q9Y2G2-5; Sequence=Displayed;
CC Name=1; Synonyms=Long, T48 {ECO:0000303|PubMed:18212821};
CC IsoId=Q9Y2G2-1; Sequence=VSP_061068, VSP_061072;
CC Name=2; Synonyms=Short;
CC IsoId=Q9Y2G2-2; Sequence=VSP_061068, VSP_061072, VSP_061073,
CC VSP_061074;
CC Name=3; Synonyms=c;
CC IsoId=Q9Y2G2-3; Sequence=VSP_061073, VSP_061074;
CC Name=4; Synonyms=T54 {ECO:0000303|PubMed:18212821}, b;
CC IsoId=Q9Y2G2-4; Sequence=VSP_061070;
CC Name=6; Synonyms=d;
CC IsoId=Q9Y2G2-6; Sequence=VSP_061071;
CC Name=7; Synonyms=T47 {ECO:0000303|PubMed:18212821};
CC IsoId=Q9Y2G2-7; Sequence=VSP_061069;
CC -!- TISSUE SPECIFICITY: High expression in lung, ovary, testis and placenta
CC (PubMed:11551959). Lower expression in heart, kidney and liver
CC (PubMed:11551959). Also expressed in spleen, lymph node and bone marrow
CC (PubMed:11821383). {ECO:0000269|PubMed:11551959,
CC ECO:0000269|PubMed:11821383}.
CC -!- DOMAIN: The disordered region is required for activation of the CARD8
CC inflammasome. {ECO:0000269|PubMed:33053349}.
CC -!- DOMAIN: [Caspase recruitment domain-containing protein 8, C-terminus]:
CC The C-terminal part of CARD8 oligomerizes to form the core of the CARD8
CC inflammasome filament: in the filament, the CARD domains form a central
CC helical filaments that are promoted by oligomerized, but flexibly
CC linked, UPA regions surrounding the filaments (PubMed:33420028,
CC PubMed:33420033). The UPA region reduces the threshold needed for
CC filament formation and signaling (PubMed:33420028, PubMed:33420033).
CC Directly recruits and polymerizes with the CARD domain of caspase-1
CC (CASP1) through the favorable side of the growing filament seed
CC (PubMed:33420033). {ECO:0000269|PubMed:33420028,
CC ECO:0000269|PubMed:33420033}.
CC -!- PTM: [Caspase recruitment domain-containing protein 8]: Undergoes
CC autocatalytic processing within the FIIND domain to generate the N-
CC terminal and C-terminal parts, which are associated non-covalently in
CC absence of pathogens and other damage-associated signals.
CC {ECO:0000269|PubMed:22087307, ECO:0000269|PubMed:33542150}.
CC -!- PTM: [Caspase recruitment domain-containing protein 8, N-terminus]:
CC Ubiquitinated by the N-end rule pathway in response to pathogens and
CC other damage-associated signals, leading to its degradation by the
CC proteasome and subsequent release of the cleaved C-terminal part of the
CC protein (Caspase recruitment domain-containing protein 8, C-terminus),
CC which polymerizes and forms the CARD8 inflammasome.
CC {ECO:0000303|PubMed:32558991, ECO:0000305|PubMed:33053349}.
CC -!- PTM: (Microbial infection) Proteolytic cleavage by HIV-1 protease in
CC the disordered region and within the ZU5 region of the FIIND domain
CC promotes ubiquitination of the N-terminal part by the N-end rule
CC pathway and degradation by the proteasome, releasing the cleaved C-
CC terminal part of the protein (Caspase recruitment domain-containing
CC protein 8, C-terminus), which polymerizes and forms the CARD8
CC inflammasome. {ECO:0000269|PubMed:33542150}.
CC -!- PTM: [Isoform 1]: Undergoes less autocatalytic processing within the
CC FIIND domain compared to isoform 5. {ECO:0000269|PubMed:33053349}.
CC -!- DISEASE: Inflammatory bowel disease 30 (IBD30) [MIM:619079]: A chronic,
CC relapsing inflammation of the gastrointestinal tract with a complex
CC etiology and a multifactorial inheritance pattern. It is subdivided
CC into Crohn disease and ulcerative colitis phenotypes. Crohn disease may
CC affect any part of the gastrointestinal tract from the mouth to the
CC anus, but most frequently it involves the terminal ileum and colon.
CC Bowel inflammation is transmural and discontinuous; it may contain
CC granulomas or be associated with intestinal or perianal fistulas. In
CC contrast, in ulcerative colitis, the inflammation is continuous and
CC limited to rectal and colonic mucosal layers; fistulas and granulomas
CC are not observed. Both diseases include extraintestinal inflammation of
CC the skin, eyes, or joints. {ECO:0000269|PubMed:17030188,
CC ECO:0000269|PubMed:19319132, ECO:0000269|PubMed:23506543,
CC ECO:0000269|PubMed:26462578, ECO:0000269|PubMed:29408806}. Note=The
CC disease may be caused by variants affecting the gene represented in
CC this entry. A number of groups have studied the possible association
CC between variant rs2043211 and inflammatory bowel disease
CC (PubMed:17030188, PubMed:19319132, PubMed:23506543, PubMed:26462578).
CC According to some studies involving a limited number of patients, this
CC variant is associated with inflammatory bowel disease (PubMed:17030188,
CC PubMed:19319132, PubMed:23506543). Such association is however not
CC confirmed in studies involving a large number of patients
CC (PubMed:26462578). Discrepancies between studies may be caused by the
CC variable consequences of this polymorphism in the different isoforms
CC (PubMed:29408806). Whereas rs2043211 introduces a stop codon after
CC 'Cys-10' (Cys10Ter) in isoform 1, and therefore the likely formation of
CC a downstream transcriptional start site for this isoform, it causes
CC Ile-102 variation in isoform 5, due to the upstream start site
CC (PubMed:29408806). Moreover, most patients bearing this polymorphism
CC continue to express the slightly smaller but fully functional isoform
CC 7, as a result of transcription downstream of the rs2043211
CC polymorphism (PubMed:29408806). {ECO:0000269|PubMed:17030188,
CC ECO:0000269|PubMed:19319132, ECO:0000269|PubMed:23506543,
CC ECO:0000269|PubMed:26462578, ECO:0000269|PubMed:29408806}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA76799.2; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/CARD8ID913ch19q13.html";
CC ---------------------------------------------------------------------------
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DR EMBL; AB023172; BAA76799.2; ALT_INIT; mRNA.
DR EMBL; AF322184; AAG50014.1; -; mRNA.
DR EMBL; AF331519; AAK01126.1; -; mRNA.
DR EMBL; AY026322; AAK08982.1; -; mRNA.
DR EMBL; AF405558; AAL02427.1; -; mRNA.
DR EMBL; EU118120; ABW96891.1; -; mRNA.
DR EMBL; EU118122; ABW96893.1; -; mRNA.
DR EMBL; AF511652; AAM46959.1; -; mRNA.
DR EMBL; AK297045; BAH12482.1; -; mRNA.
DR EMBL; AK297069; BAH12488.1; -; mRNA.
DR EMBL; AC008392; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC011466; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471177; EAW52321.1; -; Genomic_DNA.
DR EMBL; CH471177; EAW52323.1; -; Genomic_DNA.
DR EMBL; BC056891; AAH56891.1; -; mRNA.
DR CCDS; CCDS12712.2; -. [Q9Y2G2-4]
DR CCDS; CCDS54287.1; -. [Q9Y2G2-6]
DR CCDS; CCDS54288.1; -. [Q9Y2G2-3]
DR CCDS; CCDS54289.1; -. [Q9Y2G2-5]
DR RefSeq; NP_001171829.1; NM_001184900.1. [Q9Y2G2-5]
DR RefSeq; NP_001171830.1; NM_001184901.1. [Q9Y2G2-4]
DR RefSeq; NP_001171831.1; NM_001184902.1. [Q9Y2G2-3]
DR RefSeq; NP_001171832.1; NM_001184903.1. [Q9Y2G2-3]
DR RefSeq; NP_001171833.1; NM_001184904.1. [Q9Y2G2-6]
DR RefSeq; NP_055774.2; NM_014959.3. [Q9Y2G2-4]
DR RefSeq; XP_006723154.1; XM_006723091.3. [Q9Y2G2-5]
DR RefSeq; XP_006723155.1; XM_006723092.3. [Q9Y2G2-5]
DR RefSeq; XP_006723156.1; XM_006723093.3. [Q9Y2G2-5]
DR RefSeq; XP_006723158.1; XM_006723095.3.
DR RefSeq; XP_006723159.1; XM_006723096.3. [Q9Y2G2-4]
DR RefSeq; XP_006723160.1; XM_006723097.3. [Q9Y2G2-4]
DR RefSeq; XP_006723167.1; XM_006723104.3. [Q9Y2G2-1]
DR RefSeq; XP_006723169.1; XM_006723106.3. [Q9Y2G2-3]
DR RefSeq; XP_006723172.1; XM_006723109.3. [Q9Y2G2-2]
DR RefSeq; XP_006723173.1; XM_006723110.3. [Q9Y2G2-6]
DR RefSeq; XP_011524943.1; XM_011526641.2. [Q9Y2G2-5]
DR RefSeq; XP_011524944.1; XM_011526642.2.
DR RefSeq; XP_011524945.1; XM_011526643.2. [Q9Y2G2-5]
DR RefSeq; XP_011524946.1; XM_011526644.2. [Q9Y2G2-5]
DR RefSeq; XP_011524952.1; XM_011526650.2. [Q9Y2G2-3]
DR RefSeq; XP_016881972.1; XM_017026483.1. [Q9Y2G2-4]
DR RefSeq; XP_016881979.1; XM_017026490.1.
DR RefSeq; XP_016881987.1; XM_017026498.1. [Q9Y2G2-2]
DR PDB; 4IKM; X-ray; 2.46 A; A=451-537.
DR PDB; 6K9F; EM; 3.70 A; A/B/C/D/E/F/G/H/I/J/K/L=451-537.
DR PDB; 6XKJ; EM; 3.54 A; A/B/C/D/E/F/G/H/I/J/K/L/M/N/O/P=451-537.
DR PDB; 7JKQ; EM; 3.30 A; B/C=1-537.
DR PDB; 7JN7; EM; 3.30 A; B/C=1-537.
DR PDBsum; 4IKM; -.
DR PDBsum; 6K9F; -.
DR PDBsum; 6XKJ; -.
DR PDBsum; 7JKQ; -.
DR PDBsum; 7JN7; -.
DR AlphaFoldDB; Q9Y2G2; -.
DR SMR; Q9Y2G2; -.
DR BioGRID; 116564; 50.
DR CORUM; Q9Y2G2; -.
DR IntAct; Q9Y2G2; 38.
DR MINT; Q9Y2G2; -.
DR STRING; 9606.ENSP00000375767; -.
DR MEROPS; S79.001; -.
DR iPTMnet; Q9Y2G2; -.
DR PhosphoSitePlus; Q9Y2G2; -.
DR BioMuta; CARD8; -.
DR DMDM; 14424229; -.
DR EPD; Q9Y2G2; -.
DR MassIVE; Q9Y2G2; -.
DR MaxQB; Q9Y2G2; -.
DR PaxDb; Q9Y2G2; -.
DR PeptideAtlas; Q9Y2G2; -.
DR PRIDE; Q9Y2G2; -.
DR ProteomicsDB; 15473; -.
DR ProteomicsDB; 19923; -.
DR ProteomicsDB; 33792; -.
DR ProteomicsDB; 85761; -. [Q9Y2G2-1]
DR ProteomicsDB; 85762; -. [Q9Y2G2-2]
DR ProteomicsDB; 85763; -. [Q9Y2G2-3]
DR Antibodypedia; 18287; 312 antibodies from 34 providers.
DR DNASU; 22900; -.
DR Ensembl; ENST00000391898.7; ENSP00000375767.3; ENSG00000105483.18. [Q9Y2G2-5]
DR Ensembl; ENST00000447740.6; ENSP00000391248.2; ENSG00000105483.18. [Q9Y2G2-4]
DR Ensembl; ENST00000519332.5; ENSP00000430108.1; ENSG00000105483.18. [Q9Y2G2-6]
DR Ensembl; ENST00000519940.6; ENSP00000428883.1; ENSG00000105483.18. [Q9Y2G2-5]
DR Ensembl; ENST00000520007.5; ENSP00000427727.1; ENSG00000105483.18. [Q9Y2G2-6]
DR Ensembl; ENST00000520015.5; ENSP00000430747.1; ENSG00000105483.18. [Q9Y2G2-3]
DR Ensembl; ENST00000520153.5; ENSP00000428736.1; ENSG00000105483.18. [Q9Y2G2-4]
DR Ensembl; ENST00000520753.5; ENSP00000429839.1; ENSG00000105483.18. [Q9Y2G2-3]
DR Ensembl; ENST00000521613.5; ENSP00000427858.1; ENSG00000105483.18. [Q9Y2G2-4]
DR Ensembl; ENST00000522431.5; ENSP00000427922.1; ENSG00000105483.18. [Q9Y2G2-6]
DR Ensembl; ENST00000651546.1; ENSP00000499211.1; ENSG00000105483.18. [Q9Y2G2-5]
DR GeneID; 22900; -.
DR KEGG; hsa:22900; -.
DR MANE-Select; ENST00000651546.1; ENSP00000499211.1; NM_001184900.3; NP_001171829.1.
DR UCSC; uc002pih.5; human. [Q9Y2G2-5]
DR UCSC; uc002pij.3; human.
DR CTD; 22900; -.
DR DisGeNET; 22900; -.
DR GeneCards; CARD8; -.
DR HGNC; HGNC:17057; CARD8.
DR HPA; ENSG00000105483; Low tissue specificity.
DR MalaCards; CARD8; -.
DR MIM; 609051; gene.
DR MIM; 619079; phenotype.
DR neXtProt; NX_Q9Y2G2; -.
DR OpenTargets; ENSG00000105483; -.
DR PharmGKB; PA134916154; -.
DR VEuPathDB; HostDB:ENSG00000105483; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00830000128447; -.
DR HOGENOM; CLU_037186_1_0_1; -.
DR InParanoid; Q9Y2G2; -.
DR OMA; QESEETW; -.
DR OrthoDB; 559093at2759; -.
DR PhylomeDB; Q9Y2G2; -.
DR TreeFam; TF352798; -.
DR PathwayCommons; Q9Y2G2; -.
DR Reactome; R-HSA-111458; Formation of apoptosome.
DR Reactome; R-HSA-9627069; Regulation of the apoptosome activity.
DR SignaLink; Q9Y2G2; -.
DR SIGNOR; Q9Y2G2; -.
DR BioGRID-ORCS; 22900; 16 hits in 1079 CRISPR screens.
DR ChiTaRS; CARD8; human.
DR GeneWiki; CARD8; -.
DR GenomeRNAi; 22900; -.
DR Pharos; Q9Y2G2; Tbio.
DR PRO; PR:Q9Y2G2; -.
DR Proteomes; UP000005640; Chromosome 19.
DR RNAct; Q9Y2G2; protein.
DR Bgee; ENSG00000105483; Expressed in monocyte and 171 other tissues.
DR ExpressionAtlas; Q9Y2G2; baseline and differential.
DR Genevisible; Q9Y2G2; HS.
DR GO; GO:0140634; C:CARD8 inflammasome complex; IDA:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0061702; C:inflammasome complex; IDA:UniProtKB.
DR GO; GO:0072559; C:NLRP3 inflammasome complex; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HGNC-UCL.
DR GO; GO:0032991; C:protein-containing complex; IDA:UniProtKB.
DR GO; GO:0050700; F:CARD domain binding; IPI:UniProtKB.
DR GO; GO:0140608; F:cysteine-type endopeptidase activator activity; IDA:UniProtKB.
DR GO; GO:0008656; F:cysteine-type endopeptidase activator activity involved in apoptotic process; IDA:HGNC-UCL.
DR GO; GO:0004175; F:endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0032089; F:NACHT domain binding; IPI:HGNC-UCL.
DR GO; GO:0038187; F:pattern recognition receptor activity; IDA:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; IEA:UniProtKB-KW.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:HGNC-UCL.
DR GO; GO:0043621; F:protein self-association; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0140374; P:antiviral innate immune response; IDA:UniProtKB.
DR GO; GO:0140633; P:CARD8 inflammasome complex assembly; IDA:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; IEA:UniProtKB-KW.
DR GO; GO:0097340; P:inhibition of cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB signaling; IDA:HGNC-UCL.
DR GO; GO:0032691; P:negative regulation of interleukin-1 beta production; IDA:UniProtKB.
DR GO; GO:0031665; P:negative regulation of lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB.
DR GO; GO:0032088; P:negative regulation of NF-kappaB transcription factor activity; IMP:UniProtKB.
DR GO; GO:1900226; P:negative regulation of NLRP3 inflammasome complex assembly; IDA:UniProtKB.
DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; IMP:UniProtKB.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IDA:HGNC-UCL.
DR GO; GO:0051260; P:protein homooligomerization; IDA:UniProtKB.
DR GO; GO:0070269; P:pyroptosis; IDA:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0097264; P:self proteolysis; IDA:UniProtKB.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR001315; CARD.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR025307; FIIND_dom.
DR Pfam; PF00619; CARD; 1.
DR Pfam; PF13553; FIIND; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50209; CARD; 1.
DR PROSITE; PS51830; FIIND; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cytoplasm; Direct protein sequencing;
KW Disease variant; Host-virus interaction; Hydrolase; Immunity; Inflammasome;
KW Inflammatory response; Innate immunity; Necrosis; Nucleus; Protease;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1..537
FT /note="Caspase recruitment domain-containing protein 8"
FT /id="PRO_0000144080"
FT CHAIN 1..296
FT /note="Caspase recruitment domain-containing protein 8, N-
FT terminus"
FT /id="PRO_0000452847"
FT CHAIN 297..537
FT /note="Caspase recruitment domain-containing protein 8, C-
FT terminus"
FT /id="PRO_0000452848"
FT DOMAIN 161..446
FT /note="FIIND"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174"
FT DOMAIN 446..536
FT /note="CARD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00046"
FT REGION 1..28
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 113..133
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 161..296
FT /note="ZU5"
FT /evidence="ECO:0000303|PubMed:22087307"
FT REGION 297..446
FT /note="UPA"
FT /evidence="ECO:0000303|PubMed:22087307"
FT COMPBIAS 1..26
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 115..133
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 59..60
FT /note="(Microbial infection) Cleavage; by HIV-1 protease"
FT /evidence="ECO:0000269|PubMed:33542150"
FT SITE 296..297
FT /note="Cleavage; by autolysis"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01174,
FT ECO:0000269|PubMed:22087307, ECO:0000269|PubMed:32051255,
FT ECO:0000269|PubMed:33542150"
FT VAR_SEQ 1..130
FT /note="MEKKECPEKSSSSEEELPRRDSGSSRNIDASKLIRLQGSRKLLVDNSIRELQ
FT YTKTGIFFQAEACVTNDTVYRELPCVSETLCDISHFFQEDDETEAEPLLFRAVPECQLS
FT GGDIPSVSEEQESSEGQDS -> MMRQRQSHYCSVLFLSVNYLGGTFP (in
FT isoform 1 and isoform 2)"
FT /id="VSP_061068"
FT VAR_SEQ 1..116
FT /note="MEKKECPEKSSSSEEELPRRDSGSSRNIDASKLIRLQGSRKLLVDNSIRELQ
FT YTKTGIFFQAEACVTNDTVYRELPCVSETLCDISHFFQEDDETEAEPLLFRAVPECQLS
FT GGDIP -> MGIPTS (in isoform 7)"
FT /id="VSP_061069"
FT VAR_SEQ 21..70
FT /note="Missing (in isoform 4)"
FT /id="VSP_061070"
FT VAR_SEQ 71..537
FT /note="Missing (in isoform 6)"
FT /id="VSP_061071"
FT VAR_SEQ 258
FT /note="Missing (in isoform 1 and isoform 2)"
FT /id="VSP_061072"
FT VAR_SEQ 388..392
FT /note="ELKLS -> WISSL (in isoform 3 and isoform 2)"
FT /id="VSP_061073"
FT VAR_SEQ 393..537
FT /note="Missing (in isoform 3 and isoform 2)"
FT /id="VSP_061074"
FT VARIANT 44
FT /note="V -> I (in IBD30; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:29408806"
FT /id="VAR_084560"
FT VARIANT 102
FT /note="F -> I (in IBD30; dbSNP:rs2043211)"
FT /evidence="ECO:0000269|PubMed:17030188,
FT ECO:0000269|PubMed:19319132, ECO:0000269|PubMed:23506543,
FT ECO:0000269|PubMed:26462578"
FT /id="VAR_084561"
FT VARIANT 173
FT /note="I -> V (in dbSNP:rs11881179)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_048606"
FT VARIANT 204
FT /note="E -> A (in dbSNP:rs59878320)"
FT /evidence="ECO:0000269|PubMed:14702039"
FT /id="VAR_061079"
FT MUTAGEN 51
FT /note="L->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 52
FT /note="Q->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 53
FT /note="Y->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 54
FT /note="T->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 55
FT /note="K->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 56
FT /note="T->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 57
FT /note="G->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 58
FT /note="I->A: Does not affect cleavage by HIV-1 protease."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 59
FT /note="F->A: Abolished cleavage by HIV-1 protease, leading
FT to prevent formation of the CARD8 inflammasome and
FT subsequent pyroptosis."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 60
FT /note="F->A: Abolished cleavage by HIV-1 protease, leading
FT to prevent formation of the CARD8 inflammasome and
FT subsequent pyroptosis."
FT /evidence="ECO:0000269|PubMed:33542150"
FT MUTAGEN 157
FT /note="K->R: Does not affect sensitivity to Val-boroPro."
FT /evidence="ECO:0000269|PubMed:33053349"
FT MUTAGEN 240
FT /note="E->A: No effect on autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 242
FT /note="E->A: No effect on autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 252
FT /note="H->A: Severe loss of autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 270
FT /note="H->A: Severe loss of autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 274
FT /note="E->R: Abolished interaction with DPP9, without
FT affecting autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:34019797"
FT MUTAGEN 279
FT /note="E->A: Partial loss of autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 280
FT /note="H->A: No effect on autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 295
FT /note="S->A: Partial loss of autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 295
FT /note="S->Q: No effect on autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 296
FT /note="F->H: Severe loss of autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 297
FT /note="S->A: Complete loss of autocatalytic cleavage.
FT Abolished ability to form the CARD8 inflammasome and
FT trigger pyroptosis. Abolished sensitivity to Val-boroPro.
FT Does not affect interaction with DPP9."
FT /evidence="ECO:0000269|PubMed:22087307,
FT ECO:0000269|PubMed:29967349, ECO:0000269|PubMed:31525884,
FT ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:33542150,
FT ECO:0000269|PubMed:34019797"
FT MUTAGEN 333
FT /note="H->A: No effect on autocatalytic cleavage."
FT /evidence="ECO:0000269|PubMed:22087307"
FT MUTAGEN 368
FT /note="L->G: Does not affect autocatalytic cleavage; does
FT not affect interaction with DPP9; impaired interaction with
FT the C-terminal fragment of CARD8 in the ternary complex."
FT /evidence="ECO:0000269|PubMed:34019797"
FT MUTAGEN 370
FT /note="F->G: Does not affect autocatalytic cleavage; does
FT not affect interaction with DPP9; impaired interaction with
FT the C-terminal fragment of CARD8 in the ternary complex."
FT /evidence="ECO:0000269|PubMed:34019797"
FT MUTAGEN 394
FT /note="R->E: Does not affect autocatalytic cleavage; does
FT not affect interaction with DPP9; impaired interaction with
FT the C-terminal fragment of CARD8 in the ternary complex."
FT /evidence="ECO:0000269|PubMed:34019797"
FT MUTAGEN 405
FT /note="F->G: Does not affect autocatalytic cleavage; does
FT not affect interaction with DPP9; impaired interaction with
FT the C-terminal fragment of CARD8 in the ternary complex."
FT /evidence="ECO:0000269|PubMed:34019797"
FT MUTAGEN 459
FT /note="R->E: Abolished formation of inflammasome filaments.
FT Abolished ability to induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:33420033"
FT MUTAGEN 464
FT /note="R->E: Abolished formation of inflammasome filaments.
FT Abolished ability to induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:33420033"
FT MUTAGEN 472
FT /note="L->R: Inhibits homodimer formation."
FT /evidence="ECO:0000269|PubMed:12067710"
FT MUTAGEN 485
FT /note="E->R: Abolished formation of inflammasome filaments.
FT Abolished ability to induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:33420033"
FT MUTAGEN 490
FT /note="E->R: Abolished formation of inflammasome
FT filaments."
FT /evidence="ECO:0000269|PubMed:33420033"
FT MUTAGEN 495
FT /note="R->E: Abolished formation of inflammasome filaments.
FT Abolished ability to induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:33420033"
FT MUTAGEN 511
FT /note="D->K: Abolished formation of inflammasome filaments.
FT Reduced ability to induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:33420033"
FT MUTAGEN 527
FT /note="Y->A: Abolished formation of inflammasome filaments.
FT Abolished ability to induce pyroptosis."
FT /evidence="ECO:0000269|PubMed:33420033"
FT CONFLICT 84
FT /note="D -> G (in Ref. 6; ABW96891)"
FT /evidence="ECO:0000305"
FT CONFLICT 107
FT /note="E -> D (in Ref. 6; ABW96891)"
FT /evidence="ECO:0000305"
FT CONFLICT 165
FT /note="E -> G (in Ref. 5; AAL02427)"
FT /evidence="ECO:0000305"
FT CONFLICT 253
FT /note="F -> S (in Ref. 11; AAH56891)"
FT /evidence="ECO:0000305"
FT CONFLICT 325
FT /note="P -> R (in Ref. 8; BAH12488)"
FT /evidence="ECO:0000305"
FT CONFLICT 432
FT /note="V -> M (in Ref. 5; AAL02427)"
FT /evidence="ECO:0000305"
FT CONFLICT 523
FT /note="E -> G (in Ref. 6; ABW96891/ABW96893)"
FT /evidence="ECO:0000305"
FT CONFLICT 528
FT /note="L -> P (in Ref. 5; AAL02427)"
FT /evidence="ECO:0000305"
FT STRAND 171..174
FT /evidence="ECO:0007829|PDB:7JKQ"
FT TURN 175..178
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 179..184
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 186..188
FT /evidence="ECO:0007829|PDB:7JKQ"
FT TURN 193..196
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 197..201
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 205..212
FT /evidence="ECO:0007829|PDB:7JKQ"
FT HELIX 214..217
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 220..224
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 234..238
FT /evidence="ECO:0007829|PDB:7JKQ"
FT TURN 241..244
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 245..251
FT /evidence="ECO:0007829|PDB:7JKQ"
FT HELIX 263..265
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 266..271
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 273..279
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 286..293
FT /evidence="ECO:0007829|PDB:7JKQ"
FT HELIX 318..320
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 326..334
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 337..345
FT /evidence="ECO:0007829|PDB:7JKQ"
FT HELIX 349..359
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 381..388
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 396..398
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 404..406
FT /evidence="ECO:0007829|PDB:7JN7"
FT STRAND 420..427
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 429..432
FT /evidence="ECO:0007829|PDB:7JKQ"
FT STRAND 434..441
FT /evidence="ECO:0007829|PDB:7JKQ"
FT HELIX 451..456
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 458..464
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 469..477
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 483..491
FT /evidence="ECO:0007829|PDB:4IKM"
FT STRAND 492..494
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 495..507
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 511..524
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 526..530
FT /evidence="ECO:0007829|PDB:4IKM"
FT HELIX 533..537
FT /evidence="ECO:0007829|PDB:4IKM"
FT VARIANT Q9Y2G2-1:10..431
FT /note="Missing (in IBD30; dbSNP:rs2043211)"
FT /evidence="ECO:0000269|PubMed:17030188,
FT ECO:0000269|PubMed:19319132, ECO:0000269|PubMed:23506543,
FT ECO:0000269|PubMed:26462578"
FT /id="VAR_084562"
FT MUTAGEN Q9Y2G2-1:152
FT /note="Q->QA: Increased autocalalytic cleavage."
FT /evidence="ECO:0000269|PubMed:33053349"
SQ SEQUENCE 537 AA; 60652 MW; 55775D025C5461BE CRC64;
MEKKECPEKS SSSEEELPRR DSGSSRNIDA SKLIRLQGSR KLLVDNSIRE LQYTKTGIFF
QAEACVTNDT VYRELPCVSE TLCDISHFFQ EDDETEAEPL LFRAVPECQL SGGDIPSVSE
EQESSEGQDS GDICSEENQI VSSYASKVCF EIEEDYKNRQ FLGPEGNVDV ELIDKSTNRY
SVWFPTAGWY LWSATGLGFL VRDEVTVTIA FGSWSQHLAL DLQHHEQWLV GGPLFDVTAE
PEEAVAEIHL PHFISLQAGE VDVSWFLVAH FKNEGMVLEH PARVEPFYAV LESPSFSLMG
ILLRIASGTR LSIPITSNTL IYYHPHPEDI KFHLYLVPSD ALLTKAIDDE EDRFHGVRLQ
TSPPMEPLNF GSSYIVSNSA NLKVMPKELK LSYRSPGEIQ HFSKFYAGQM KEPIQLEITE
KRHGTLVWDT EVKPVDLQLV AASAPPPFSG AAFVKENHRQ LQARMGDLKG VLDDLQDNEV
LTENEKELVE QEKTRQSKNE ALLSMVEKKG DLALDVLFRS ISERDPYLVS YLRQQNL
