ZBP1_MOUSE
ID ZBP1_MOUSE Reviewed; 411 AA.
AC Q9QY24; Q8VE02; Q9D8B9;
DT 25-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Z-DNA-binding protein 1 {ECO:0000303|PubMed:17618271};
DE AltName: Full=DNA-dependent activator of IFN-regulatory factors {ECO:0000303|PubMed:17618271};
DE Short=DAI {ECO:0000303|PubMed:17618271};
DE AltName: Full=Tumor stroma and activated macrophage protein DLM-1 {ECO:0000303|PubMed:10564822};
GN Name=Zbp1 {ECO:0000303|PubMed:17618271, ECO:0000312|MGI:MGI:1927449};
GN Synonyms=Dlm1 {ECO:0000303|PubMed:10564822};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND INDUCTION.
RC STRAIN=C3Heb/FeJ; TISSUE=Liver;
RX PubMed=10564822; DOI=10.1016/s0378-1119(99)00419-9;
RA Fu Y., Comella N., Tognazzi K., Brown L.F., Dvorak H.F., Kocher O.;
RT "Cloning of DLM-1, a novel gene that is up-regulated in activated
RT macrophages, using RNA differential display.";
RL Gene 240:157-163(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=C57BL/6J; TISSUE=Small intestine;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Mammary tumor;
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 [4]
RP FUNCTION.
RX PubMed=17618271; DOI=10.1038/nature06013;
RA Takaoka A., Wang Z., Choi M.K., Yanai H., Negishi H., Ban T., Lu Y.,
RA Miyagishi M., Kodama T., Honda K., Ohba Y., Taniguchi T.;
RT "DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate
RT immune response.";
RL Nature 448:501-505(2007).
RN [5]
RP FUNCTION, SUBUNIT, PHOSPHORYLATION, AND MUTAGENESIS OF 352-SER-SER-353.
RX PubMed=18375758; DOI=10.1073/pnas.0801295105;
RA Wang Z., Choi M.K., Ban T., Yanai H., Negishi H., Lu Y., Tamura T.,
RA Takaoka A., Nishikura K., Taniguchi T.;
RT "Regulation of innate immune responses by DAI (DLM-1/ZBP1) and other DNA-
RT sensing molecules.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:5477-5482(2008).
RN [6]
RP FUNCTION, AND INTERACTION WITH RIPK1; RIPK3 AND MURID HERPESVIRUS 1 RIR1
RP (MICROBIAL INFECTION).
RX PubMed=19590578; DOI=10.1038/embor.2009.109;
RA Rebsamen M., Heinz L.X., Meylan E., Michallet M.C., Schroder K.,
RA Hofmann K., Vazquez J., Benedict C.A., Tschopp J.;
RT "DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs
RT to activate NF-kappaB.";
RL EMBO Rep. 10:916-922(2009).
RN [7]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19144319; DOI=10.1016/j.immuni.2008.11.006;
RA Trost M., English L., Lemieux S., Courcelles M., Desjardins M.,
RA Thibault P.;
RT "The phagosomal proteome in interferon-gamma-activated macrophages.";
RL Immunity 30:143-154(2009).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver, and Spleen;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [9]
RP FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH RIPK3.
RX PubMed=22423968; DOI=10.1016/j.chom.2012.01.016;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed
RT necrosis that is targeted by murine cytomegalovirus vIRA.";
RL Cell Host Microbe 11:290-297(2012).
RN [10]
RP ERRATUM OF PUBMED:22423968.
RX PubMed=31600504; DOI=10.1016/j.chom.2019.09.004;
RA Upton J.W., Kaiser W.J., Mocarski E.S.;
RT "DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed
RT necrosis that is targeted by murine cytomegalovirus vIRA.";
RL Cell Host Microbe 26:564-564(2019).
RN [11]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH RIPK1.
RX PubMed=23283962; DOI=10.1128/jvi.02860-12;
RA Pham T.H., Kwon K.M., Kim Y.E., Kim K.K., Ahn J.H.;
RT "DNA sensing-independent inhibition of herpes simplex virus 1 replication
RT by DAI/ZBP1.";
RL J. Virol. 87:3076-3086(2013).
RN [12]
RP FUNCTION, INTERACTION WITH RIPK3, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF
RP 122-ASN--TYR-126.
RX PubMed=27746097; DOI=10.1016/j.chom.2016.09.014;
RA Thapa R.J., Ingram J.P., Ragan K.B., Nogusa S., Boyd D.F., Benitez A.A.,
RA Sridharan H., Kosoff R., Shubina M., Landsteiner V.J., Andrake M.,
RA Vogel P., Sigal L.J., tenOever B.R., Thomas P.G., Upton J.W.,
RA Balachandran S.;
RT "DAI senses influenza A virus genomic RNA and activates RIPK3-dependent
RT cell death.";
RL Cell Host Microbe 20:674-681(2016).
RN [13]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=27917412; DOI=10.1126/sciimmunol.aag2045;
RA Kuriakose T., Man S.M., Malireddi R.K., Karki R., Kesavardhana S.,
RA Place D.E., Neale G., Vogel P., Kanneganti T.D.;
RT "ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3
RT inflammasome and programmed cell death pathways.";
RL Sci. Immunol. 1:0-0(2016).
RN [14]
RP FUNCTION, ACTIVITY REGULATION, DISRUPTION PHENOTYPE, AND INTERACTION WITH
RP RIPK3.
RX PubMed=27819681; DOI=10.1038/nature20558;
RA Lin J., Kumari S., Kim C., Van T.M., Wachsmuth L., Polykratis A.,
RA Pasparakis M.;
RT "RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation.";
RL Nature 540:124-128(2016).
RN [15]
RP FUNCTION, ACTIVITY REGULATION, DISRUPTION PHENOTYPE, AND INTERACTION WITH
RP RIPK3.
RX PubMed=27819682; DOI=10.1038/nature20559;
RA Newton K., Wickliffe K.E., Maltzman A., Dugger D.L., Strasser A.,
RA Pham V.C., Lill J.R., Roose-Girma M., Warming S., Solon M., Ngu H.,
RA Webster J.D., Dixit V.M.;
RT "RIPK1 inhibits ZBP1-driven necroptosis during development.";
RL Nature 540:129-133(2016).
RN [16]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF 46-ASN--TYR-50 AND 122-ASN--TYR-126.
RX PubMed=28716805; DOI=10.15252/embj.201796476;
RA Maelfait J., Liverpool L., Bridgeman A., Ragan K.B., Upton J.W.,
RA Rehwinkel J.;
RT "Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis.";
RL EMBO J. 36:2529-2543(2017).
RN [17]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RIPK3, DOMAIN, AND
RP MUTAGENESIS OF 46-ASN--TYR-50; 122-ASN--TYR-126; 192-ILE--GLY-195 AND
RP 248-VAL--GLY-251.
RX PubMed=28607035; DOI=10.15252/embr.201743947;
RA Sridharan H., Ragan K.B., Guo H., Gilley R.P., Landsteiner V.J.,
RA Kaiser W.J., Upton J.W.;
RT "Murine cytomegalovirus IE3-dependent transcription is required for
RT DAI/ZBP1-mediated necroptosis.";
RL EMBO Rep. 18:1429-1441(2017).
RN [18]
RP UBIQUITINATION AT LYS-17 AND LYS-43.
RX PubMed=28634194; DOI=10.1084/jem.20170550;
RA Kesavardhana S., Kuriakose T., Guy C.S., Samir P., Malireddi R.K.S.,
RA Mishra A., Kanneganti T.D.;
RT "ZBP1/DAI ubiquitination and sensing of influenza vRNPs activate programmed
RT cell death.";
RL J. Exp. Med. 214:2217-2229(2017).
RN [19]
RP FUNCTION, INDUCTION, AND INTERACTION WITH VACCINIA VIRUS PROTEIN E3.
RX PubMed=29073079; DOI=10.1073/pnas.1700999114;
RA Koehler H., Cotsmire S., Langland J., Kibler K.V., Kalman D., Upton J.W.,
RA Mocarski E.S., Jacobs B.L.;
RT "Inhibition of DAI-dependent necroptosis by the Z-DNA binding domain of the
RT vaccinia virus innate immune evasion protein, E3.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:11506-11511(2017).
RN [20]
RP FUNCTION, AND MUTAGENESIS OF 46-ASN--TYR-50; 122-ASN--TYR-126;
RP 192-ILE--GLY-195 AND 248-VAL--GLY-251.
RX PubMed=30050136; DOI=10.1038/s41419-018-0868-3;
RA Guo H., Gilley R.P., Fisher A., Lane R., Landsteiner V.J., Ragan K.B.,
RA Dovey C.M., Carette J.E., Upton J.W., Mocarski E.S., Kaiser W.J.;
RT "Species-independent contribution of ZBP1/DAI/DLM-1-triggered necroptosis
RT in host defense against HSV1.";
RL Cell Death Dis. 9:816-816(2018).
RN [21]
RP INDUCTION.
RX PubMed=29321274; DOI=10.4049/jimmunol.1701538;
RA Kuriakose T., Zheng M., Neale G., Kanneganti T.D.;
RT "IRF1 is a transcriptional regulator of ZBP1 promoting NLRP3 inflammasome
RT activation and cell death during influenza virus infection.";
RL J. Immunol. 200:1489-1495(2018).
RN [22]
RP REVIEW.
RX PubMed=29236673; DOI=10.1016/j.it.2017.11.002;
RA Kuriakose T., Kanneganti T.D.;
RT "ZBP1: innate sensor regulating cell death and inflammation.";
RL Trends Immunol. 39:123-134(2018).
RN [23]
RP FUNCTION.
RX PubMed=30635240; DOI=10.1016/j.immuni.2018.11.017;
RA Daniels B.P., Kofman S.B., Smith J.R., Norris G.T., Snyder A.G., Kolb J.P.,
RA Gao X., Locasale J.W., Martinez J., Gale M. Jr., Loo Y.M., Oberst A.;
RT "The nucleotide sensor ZBP1 and kinase RIPK3 induce the enzyme IRG1 to
RT promote an antiviral metabolic state in neurons.";
RL Immunity 50:64-76(2019).
RN [24]
RP FUNCTION, AND INTERACTION WITH MURID HERPESVIRUS 1 RIR1 (MICROBIAL
RP INFECTION).
RX PubMed=30498077; DOI=10.15252/embr.201846518;
RA Pham C.L., Shanmugam N., Strange M., O'Carroll A., Brown J.W., Sierecki E.,
RA Gambin Y., Steain M., Sunde M.;
RT "Viral M45 and necroptosis-associated proteins form heteromeric amyloid
RT assemblies.";
RL EMBO Rep. 20:0-0(2019).
RN [25]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=31358656; DOI=10.4049/jimmunol.1900216;
RA Ingram J.P., Thapa R.J., Fisher A., Tummers B., Zhang T., Yin C.,
RA Rodriguez D.A., Guo H., Lane R., Williams R., Slifker M.J.,
RA Basagoudanavar S.H., Rall G.F., Dillon C.P., Green D.R., Kaiser W.J.,
RA Balachandran S.;
RT "ZBP1/DAI Drives RIPK3-Mediated Cell Death Induced by IFNs in the Absence
RT of RIPK1.";
RL J. Immunol. 203:1348-1355(2019).
RN [26]
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH RIPK3, DISRUPTION
RP PHENOTYPE, DOMAIN, AND MUTAGENESIS OF 192-ILE--GLY-195.
RX PubMed=32200799; DOI=10.1016/j.cell.2020.02.050;
RA Zhang T., Yin C., Boyd D.F., Quarato G., Ingram J.P., Shubina M.,
RA Ragan K.B., Ishizuka T., Crawford J.C., Tummers B., Rodriguez D.A., Xue J.,
RA Peri S., Kaiser W.J., Lopez C.B., Xu Y., Upton J.W., Thomas P.G.,
RA Green D.R., Balachandran S.;
RT "Influenza virus Z-RNAs induce ZBP1-mediated necroptosis.";
RL Cell 180:1115-1129(2020).
RN [27]
RP FUNCTION.
RX PubMed=31630209; DOI=10.1093/intimm/dxz070;
RA Momota M., Lelliott P., Kubo A., Kusakabe T., Kobiyama K., Kuroda E.,
RA Imai Y., Akira S., Coban C., Ishii K.J.;
RT "ZBP1 governs the inflammasome-independent IL-1alpha and neutrophil
RT inflammation that play a dual role in anti-influenza virus immunity.";
RL Int. Immunol. 32:203-212(2020).
RN [28]
RP FUNCTION.
RX PubMed=32298652; DOI=10.1016/j.cell.2020.03.040;
RA Zheng M., Karki R., Vogel P., Kanneganti T.D.;
RT "Caspase-6 is a key regulator of innate immunity, inflammasome activation,
RT and host defense.";
RL Cell 181:674-687(2020).
RN [29]
RP FUNCTION, DOMAIN, AND MUTAGENESIS OF 77-ALA--GLY-150.
RX PubMed=32350114; DOI=10.1074/jbc.ra120.013752;
RA Kesavardhana S., Malireddi R.K.S., Burton A.R., Porter S.N., Vogel P.,
RA Pruett-Miller S.M., Kanneganti T.D.;
RT "The Zalpha2 domain of ZBP1 is a molecular switch regulating influenza-
RT induced PANoptosis and perinatal lethality during development.";
RL J. Biol. Chem. 295:8325-8330(2020).
RN [30]
RP FUNCTION, AND DOMAIN.
RX PubMed=33109609; DOI=10.1074/jbc.ra120.015924;
RA Banoth B., Tuladhar S., Karki R., Sharma B.R., Briard B., Kesavardhana S.,
RA Burton A., Kanneganti T.D.;
RT "ZBP1 promotes fungi-induced inflammasome activation and pyroptosis,
RT apoptosis, and necroptosis (PANoptosis).";
RL J. Biol. Chem. 295:18276-18283(2020).
RN [31]
RP FUNCTION.
RX PubMed=32315377; DOI=10.1084/jem.20191913;
RA Devos M., Tanghe G., Gilbert B., Dierick E., Verheirstraeten M.,
RA Nemegeer J., de Reuver R., Lefebvre S., De Munck J., Rehwinkel J.,
RA Vandenabeele P., Declercq W., Maelfait J.;
RT "Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte
RT necroptosis and skin inflammation.";
RL J. Exp. Med. 217:0-0(2020).
RN [32]
RP FUNCTION, ACTIVITY REGULATION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP 46-ASN--TYR-50; 122-ASN--TYR-126 AND 192-ILE--GLY-195.
RX PubMed=32296175; DOI=10.1038/s41586-020-2129-8;
RA Jiao H., Wachsmuth L., Kumari S., Schwarzer R., Lin J., Eren R.O.,
RA Fisher A., Lane R., Young G.R., Kassiotis G., Kaiser W.J., Pasparakis M.;
RT "Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and
RT inflammation.";
RL Nature 580:391-395(2020).
RN [33]
RP FUNCTION, AND IDENTIFICATION IN THE AIM2 PANOPTOSOME COMPLEX.
RX PubMed=34471287; DOI=10.1038/s41586-021-03875-8;
RA Lee S., Karki R., Wang Y., Nguyen L.N., Kalathur R.C., Kanneganti T.D.;
RT "AIM2 forms a complex with pyrin and ZBP1 to drive PANoptosis and host
RT defence.";
RL Nature 597:415-419(2021).
RN [34]
RP FUNCTION, AND INTERACTION WITH RIPK1.
RX PubMed=33397971; DOI=10.1038/s41467-020-20357-z;
RA Muendlein H.I., Connolly W.M., Magri Z., Smirnova I., Ilyukha V.,
RA Gautam A., Degterev A., Poltorak A.;
RT "ZBP1 promotes LPS-induced cell death and IL-1beta release via RHIM-
RT mediated interactions with RIPK1.";
RL Nat. Commun. 12:86-86(2021).
RN [35]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 8-70, AND DNA-BINDING.
RX PubMed=11524677; DOI=10.1038/nsb0901-761;
RA Schwartz T., Behlke J., Lowenhaupt K., Heinemann U., Rich A.;
RT "Structure of the DLM-1-Z-DNA complex reveals a conserved family of Z-DNA-
RT binding proteins.";
RL Nat. Struct. Biol. 8:761-765(2001).
CC -!- FUNCTION: Key innate sensor that recognizes and binds Z-RNA structures,
CC which are produced by a number of viruses, such as herpesvirus,
CC orthomyxovirus or flavivirus, and triggers different forms of cell
CC death (PubMed:17618271, PubMed:18375758, PubMed:19590578,
CC PubMed:23283962, PubMed:27746097, PubMed:27917412, PubMed:27819681,
CC PubMed:28716805, PubMed:28607035, PubMed:30050136, PubMed:31358656,
CC PubMed:32200799, PubMed:32296175, PubMed:30498077, PubMed:29073079).
CC ZBP1 acts as an essential mediator of pyroptosis, necroptosis and
CC apoptosis (PANoptosis), an integral part of host defense against
CC pathogens, by activating RIPK3, caspase-8 (CASP8), and the NLRP3
CC inflammasome (PubMed:27746097, PubMed:27917412, PubMed:28607035,
CC PubMed:32200799, PubMed:32298652, PubMed:32350114, PubMed:32296175).
CC Key activator of necroptosis, a programmed cell death process in
CC response to death-inducing TNF-alpha family members, via its ability to
CC bind Z-RNA: once activated upon Z-RNA-binding, ZBP1 interacts and
CC stimulates RIPK3 kinase, which phosphorylates and activates MLKL,
CC triggering execution of programmed necrosis (PubMed:22423968,
CC PubMed:27746097, PubMed:27819681, PubMed:27819682, PubMed:28716805,
CC PubMed:32200799, PubMed:32350114, PubMed:32315377, PubMed:32296175). In
CC addition to TNF-induced necroptosis, necroptosis can also take place in
CC the nucleus in response to orthomyxoviruses infection: ZBP1 recognizes
CC and binds Z-RNA structures that are produced in infected nuclei by
CC orthomyxoviruses, such as the influenza A virus (IAV), leading to ZBP1
CC activation, RIPK3 stimulation and subsequent MLKL phosphorylation,
CC triggering disruption of the nuclear envelope and leakage of cellular
CC DNA into the cytosol (PubMed:32200799, PubMed:32296175). ZBP1-dependent
CC cell death in response to IAV infection promotes interleukin-1 alpha
CC (IL1A) induction in an NLRP3-inflammasome-independent manner: IL1A
CC expression is required for the optimal interleukin-1 beta (IL1B)
CC production, and together, these cytokines promote infiltration of
CC inflammatory neutrophils to the lung, leading to the formation of
CC neutrophil extracellular traps (PubMed:31630209). In addition to its
CC direct role in driving necroptosis via its ability to sense Z-RNAs,
CC also involved in PANoptosis triggered in response to bacterial
CC infection: component of the AIM2 PANoptosome complex, a multiprotein
CC complex that triggers PANoptosis (PubMed:34471287). Also acts as the
CC apical sensor of fungal infection responsible for activating PANoptosis
CC (PubMed:33109609). Involved in CASP8-mediated cell death via its
CC interaction with RIPK1 but independently of its ability to sense Z-RNAs
CC (PubMed:33397971). In some cell types, also able to restrict viral
CC replication by promoting cell death-independent responses
CC (PubMed:30635240). In response to flavivirus infection in neurons,
CC promotes a cell death-independent pathway that restricts viral
CC replication: together with RIPK3, promotes a death-independent
CC transcriptional program that modifies the cellular metabolism via up-
CC regulation expression of the enzyme ACOD1/IRG1 and production of the
CC metabolite itaconate (PubMed:30635240). Itaconate inhibits the activity
CC of succinate dehydrogenase, generating a metabolic state in neurons
CC that suppresses replication of viral genomes (PubMed:30635240).
CC {ECO:0000269|PubMed:17618271, ECO:0000269|PubMed:18375758,
CC ECO:0000269|PubMed:19590578, ECO:0000269|PubMed:22423968,
CC ECO:0000269|PubMed:23283962, ECO:0000269|PubMed:27746097,
CC ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682,
CC ECO:0000269|PubMed:27917412, ECO:0000269|PubMed:28607035,
CC ECO:0000269|PubMed:28716805, ECO:0000269|PubMed:29073079,
CC ECO:0000269|PubMed:30050136, ECO:0000269|PubMed:30498077,
CC ECO:0000269|PubMed:30635240, ECO:0000269|PubMed:31358656,
CC ECO:0000269|PubMed:31630209, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175, ECO:0000269|PubMed:32298652,
CC ECO:0000269|PubMed:32315377, ECO:0000269|PubMed:32350114,
CC ECO:0000269|PubMed:33109609, ECO:0000269|PubMed:33397971,
CC ECO:0000269|PubMed:34471287}.
CC -!- ACTIVITY REGULATION: ZBP1-dependent necroptosis is normally inhibited
CC by RIPK1: RIPK1 inhibits the ZBP1-induced activation of RIPK3 via FADD-
CC mediated recruitment of CASP8, which cleaves RIPK1 and limits TNF-
CC induced necroptosis. {ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:31358656,
CC ECO:0000269|PubMed:32296175}.
CC -!- SUBUNIT: Homodimer (PubMed:18375758). Interacts (via RIP homotypic
CC interaction motif) with RIPK3; leading to RIPK3 activation and
CC necroptosis; interaction is enhanced by CASP6 (PubMed:19590578,
CC PubMed:22423968, PubMed:27746097, PubMed:27819681, PubMed:27819682,
CC PubMed:28607035, PubMed:32200799, PubMed:32298652). Interacts (via RIP
CC homotypic interaction motif) with RIPK1 (PubMed:19590578,
CC PubMed:23283962, PubMed:33397971). Component of the AIM2 PANoptosome
CC complex, a multiprotein complex that drives inflammatory cell death
CC (PANoptosis) (PubMed:34471287). {ECO:0000269|PubMed:18375758,
CC ECO:0000269|PubMed:19590578, ECO:0000269|PubMed:22423968,
CC ECO:0000269|PubMed:23283962, ECO:0000269|PubMed:27746097,
CC ECO:0000269|PubMed:27819681, ECO:0000269|PubMed:27819682,
CC ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32298652, ECO:0000269|PubMed:33397971,
CC ECO:0000269|PubMed:34471287}.
CC -!- SUBUNIT: (Microbial infection) Interacts (via RIP homotypic interaction
CC motif) with murid herpesvirus protein RIR1 (via RIP homotypic
CC interaction motif); leading to inhibition of ZBP1-dependent
CC necroptosis. {ECO:0000269|PubMed:19590578,
CC ECO:0000269|PubMed:30498077}.
CC -!- SUBUNIT: (Microbial infection) Interacts with vaccinia virus E3
CC protein; leading to inhibit ZBP1-dependent necroptosis.
CC {ECO:0000269|PubMed:29073079}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:23283962,
CC ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}. Nucleus {ECO:0000269|PubMed:23283962,
CC ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:32200799,
CC ECO:0000269|PubMed:32296175}. Note=Mainly cytoplasmic
CC (PubMed:32200799). Accumulates in the nucleus in response to influenza
CC A virus (IAV) infection: senses IAV defective viral genomes RNA in the
CC nucleus (PubMed:32200799). {ECO:0000269|PubMed:32200799}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9QY24-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9QY24-2; Sequence=VSP_004083, VSP_004084;
CC -!- TISSUE SPECIFICITY: Expressed in lung, spleen and liver. Lower levels
CC were seen in heart, kidney and testis. Expression is greatly up-
CC regulated in tumor stromal cells and activated macrophages.
CC {ECO:0000269|PubMed:10564822}.
CC -!- INDUCTION: Expression is activated by IRF1 (PubMed:29321274). Up-
CC regulated following interferon treatment (PubMed:10564822,
CC PubMed:29073079). By lipopolysaccharides (LPS) (PubMed:10564822).
CC {ECO:0000269|PubMed:10564822, ECO:0000269|PubMed:29073079,
CC ECO:0000269|PubMed:29321274}.
CC -!- DOMAIN: The Z-binding domains recognize and bind left-handed double-
CC stranded Z-RNA structures, but not A-RNA, the right-handed double-
CC stranded RNAs that are structurally very different from Z-RNAs
CC (PubMed:32200799). The second Z-binding domain (also named Zalpha2)
CC acts as a molecular switch regulating pyroptosis, necroptosis and
CC apoptosis (PANoptosis) (PubMed:32350114, PubMed:33109609). The second
CC Z-binding domain is essential for sensing influenza A virus (IAV) Z-
CC RNAs (PubMed:28607035, PubMed:28716805, PubMed:32350114).
CC {ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:28716805,
CC ECO:0000269|PubMed:32200799, ECO:0000269|PubMed:32350114,
CC ECO:0000269|PubMed:33109609}.
CC -!- PTM: Ubiquitinated; polyubiquitinated following influenza A virus (IAV)
CC infection. {ECO:0000269|PubMed:28634194}.
CC -!- PTM: Phosphorylated. {ECO:0000269|PubMed:18375758}.
CC -!- DISRUPTION PHENOTYPE: Mice are resistant to necroptosis, characterized
CC by a decrease in epithelial cell death and an increase in virus
CC replication (PubMed:22423968, PubMed:27746097, PubMed:27917412). At a
CC modestly lethal dose of influenza A virus (IAV), mice display
CC significantly increased rates of mortality, probably caused by a
CC failure to eliminate infected cells and limit virus spread in pulmonary
CC tissue (PubMed:32200799). Perinatal lethality observed in Ripk1
CC knockout mice is rescued in knockout mice lacking both Ripk1 and Zbp1
CC (PubMed:27819681, PubMed:27819682). Skin inflammation observed in
CC Ripk1(mRHIM) mutant mice is abrogated in Ripk1(mRHIM) mutant mice that
CC also lack Zbp1 (PubMed:27819681). {ECO:0000269|PubMed:22423968,
CC ECO:0000269|PubMed:27746097, ECO:0000269|PubMed:27819681,
CC ECO:0000269|PubMed:27819682, ECO:0000269|PubMed:27917412,
CC ECO:0000269|PubMed:32200799}.
CC -!- CAUTION: According to a report, mice lacking Zbp1 display reductions in
CC respiratory epithelial damage and lung inflammation (PubMed:27917412).
CC However, the virus persists and replicates in the infected cells
CC leading to a delay in recovery from infection, but the animals are
CC protected from mortality (PubMed:27917412). In contrast, another
CC article reported increased mortality in knockout mice, probably caused
CC by increased virus burden (PubMed:27746097). However, as this study did
CC not assess the inflammatory response in the lungs, it is difficult to
CC compare ZBP1 regulation of lung inflammation between these two studies
CC (PubMed:27746097). {ECO:0000269|PubMed:27746097,
CC ECO:0000269|PubMed:27917412}.
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DR EMBL; AF136520; AAF17234.1; -; mRNA.
DR EMBL; AK008179; BAB25513.1; -; mRNA.
DR EMBL; BC020033; AAH20033.1; -; mRNA.
DR CCDS; CCDS17142.1; -. [Q9QY24-1]
DR CCDS; CCDS50813.1; -. [Q9QY24-2]
DR RefSeq; NP_001132991.1; NM_001139519.1. [Q9QY24-2]
DR PDB; 1J75; X-ray; 1.85 A; A=8-70.
DR PDB; 2HEO; X-ray; 1.70 A; A/D=8-70.
DR PDBsum; 1J75; -.
DR PDBsum; 2HEO; -.
DR AlphaFoldDB; Q9QY24; -.
DR SMR; Q9QY24; -.
DR BioGRID; 208387; 4.
DR DIP; DIP-29879N; -.
DR IntAct; Q9QY24; 2.
DR STRING; 10090.ENSMUSP00000029018; -.
DR iPTMnet; Q9QY24; -.
DR PhosphoSitePlus; Q9QY24; -.
DR EPD; Q9QY24; -.
DR jPOST; Q9QY24; -.
DR MaxQB; Q9QY24; -.
DR PaxDb; Q9QY24; -.
DR PRIDE; Q9QY24; -.
DR ProteomicsDB; 275337; -. [Q9QY24-1]
DR ProteomicsDB; 275338; -. [Q9QY24-2]
DR Antibodypedia; 14231; 213 antibodies from 35 providers.
DR DNASU; 58203; -.
DR Ensembl; ENSMUST00000109116; ENSMUSP00000104744; ENSMUSG00000027514. [Q9QY24-2]
DR GeneID; 58203; -.
DR KEGG; mmu:58203; -.
DR UCSC; uc008odp.2; mouse. [Q9QY24-2]
DR CTD; 81030; -.
DR MGI; MGI:1927449; Zbp1.
DR VEuPathDB; HostDB:ENSMUSG00000027514; -.
DR eggNOG; ENOG502SRWE; Eukaryota.
DR GeneTree; ENSGT00390000002234; -.
DR HOGENOM; CLU_1447219_0_0_1; -.
DR InParanoid; Q9QY24; -.
DR PhylomeDB; Q9QY24; -.
DR BioGRID-ORCS; 58203; 2 hits in 75 CRISPR screens.
DR ChiTaRS; Zbp1; mouse.
DR EvolutionaryTrace; Q9QY24; -.
DR PRO; PR:Q9QY24; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q9QY24; protein.
DR Bgee; ENSMUSG00000027514; Expressed in small intestine Peyer's patch and 79 other tissues.
DR ExpressionAtlas; Q9QY24; baseline and differential.
DR Genevisible; Q9QY24; MM.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IDA:MGI.
DR GO; GO:0003726; F:double-stranded RNA adenosine deaminase activity; IEA:InterPro.
DR GO; GO:0003725; F:double-stranded RNA binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0003692; F:left-handed Z-DNA binding; IDA:MGI.
DR GO; GO:0002218; P:activation of innate immune response; IDA:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0050832; P:defense response to fungus; IMP:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:0060545; P:positive regulation of necroptotic process; IDA:UniProtKB.
DR GO; GO:0060340; P:positive regulation of type I interferon-mediated signaling pathway; IMP:MGI.
DR GO; GO:0070269; P:pyroptosis; IMP:UniProtKB.
DR GO; GO:0050727; P:regulation of inflammatory response; IMP:UniProtKB.
DR GO; GO:2000659; P:regulation of interleukin-1-mediated signaling pathway; IMP:UniProtKB.
DR Gene3D; 1.10.10.10; -; 2.
DR InterPro; IPR025735; RHIM_dom.
DR InterPro; IPR036388; WH-like_DNA-bd_sf.
DR InterPro; IPR036390; WH_DNA-bd_sf.
DR InterPro; IPR042371; Z_dom.
DR InterPro; IPR042361; ZBP1.
DR PANTHER; PTHR14966; PTHR14966; 1.
DR Pfam; PF12721; RHIM; 2.
DR Pfam; PF02295; z-alpha; 2.
DR SMART; SM00550; Zalpha; 2.
DR SUPFAM; SSF46785; SSF46785; 2.
DR PROSITE; PS50139; Z_BINDING; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Antiviral defense; Apoptosis;
KW Cytoplasm; DNA-binding; Host-virus interaction; Immunity; Innate immunity;
KW Isopeptide bond; Necrosis; Nucleus; Reference proteome; Repeat;
KW RNA-binding; Ubl conjugation.
FT CHAIN 1..411
FT /note="Z-DNA-binding protein 1"
FT /id="PRO_0000066565"
FT DOMAIN 8..70
FT /note="Z-binding 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00073"
FT DOMAIN 84..148
FT /note="Z-binding 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00073"
FT REGION 60..86
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 263..303
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 332..411
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 188..205
FT /note="RIP homotypic interaction motif (RHIM) 1"
FT /evidence="ECO:0000269|PubMed:19590578"
FT MOTIF 237..261
FT /note="RIP homotypic interaction motif (RHIM) 2"
FT /evidence="ECO:0000269|PubMed:19590578"
FT COMPBIAS 271..288
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 332..352
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 353..371
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CROSSLNK 17
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:28634194"
FT CROSSLNK 43
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:28634194"
FT VAR_SEQ 154..187
FT /note="AHSGVTQESPAIICQHNPVNMICQQGANSHISIA -> VLPCSPGCPRTHHV
FT DQAGLEPTEIFLLLPIKFWD (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_004083"
FT VAR_SEQ 188..411
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:16141072"
FT /id="VSP_004084"
FT MUTAGEN 46..50
FT /note="NQVLY->DQVLA: In ZBP1(Zalpha1); no effect. In
FT ZBP1(Zalpha1-Zalpha2); knockin mice are viable and develop
FT mild skin lesions in response to influenza A virus (IAV);
FT mice are protected from the activation of RIPK3 and MLKL as
FT well as the cell death; when associated with 122-D--A-126."
FT /evidence="ECO:0000269|PubMed:28607035,
FT ECO:0000269|PubMed:28716805, ECO:0000269|PubMed:30050136,
FT ECO:0000269|PubMed:32296175"
FT MUTAGEN 77..150
FT /note="Missing: Abolished ability to activate pyroptosis,
FT necroptosis and apoptosis (PANoptosis) in response to
FT influenza A virus (IAV) infection in knockin mice."
FT /evidence="ECO:0000269|PubMed:32350114"
FT MUTAGEN 122..126
FT /note="NPLLY->DPLLA: In ZBP1(Zalpha2); abolished ability to
FT sense influenza A virus (IAV) Z-RNAs. In ZBP1(Zalpha2);
FT knockin mice are viable and develop mild skin lesions in
FT response to influenza A virus (IAV). ZBP1(Zalpha2) knockin
FT mice are protected from the activation of RIPK3 and MLKL as
FT well as the cell death. In ZBP1(Zalpha1-Zalpha2); knockin
FT mice are viable and develop mild skin lesions in response
FT to influenza A virus (IAV); mice are protected from the
FT activation of RIPK3 and MLKL as well as the cell death;
FT when associated with 46-D--A-50."
FT /evidence="ECO:0000269|PubMed:27746097,
FT ECO:0000269|PubMed:28607035, ECO:0000269|PubMed:28716805,
FT ECO:0000269|PubMed:30050136, ECO:0000269|PubMed:32296175"
FT MUTAGEN 192..195
FT /note="IQIG->AAAA: In mRHIMA; abolished interaction with
FT RIPK3 and subsequent necroptosis. In ZBP1(Mr1) knockin mice
FT are viable and do not develop skin inflammation in response
FT to lethal dose of influenza A virus (IAV)."
FT /evidence="ECO:0000269|PubMed:28607035,
FT ECO:0000269|PubMed:30050136, ECO:0000269|PubMed:32200799,
FT ECO:0000269|PubMed:32296175"
FT MUTAGEN 248..251
FT /note="VQLG->AAAA: In mRHIMB; does not affect ability to
FT induce necroptosis."
FT /evidence="ECO:0000269|PubMed:28607035,
FT ECO:0000269|PubMed:30050136"
FT MUTAGEN 352..353
FT /note="SS->AA: Does not greatly affect phosphorylation
FT status."
FT /evidence="ECO:0000269|PubMed:18375758"
FT CONFLICT 67
FT /note="S -> R (in Ref. 3; AAH20033)"
FT /evidence="ECO:0000305"
FT CONFLICT 83
FT /note="N -> D (in Ref. 3; AAH20033)"
FT /evidence="ECO:0000305"
FT CONFLICT 197
FT /note="G -> R (in Ref. 3; AAH20033)"
FT /evidence="ECO:0000305"
FT CONFLICT 293
FT /note="F -> S (in Ref. 3; AAH20033)"
FT /evidence="ECO:0000305"
FT CONFLICT 403
FT /note="S -> T (in Ref. 3; AAH20033)"
FT /evidence="ECO:0000305"
FT HELIX 13..25
FT /evidence="ECO:0007829|PDB:2HEO"
FT HELIX 31..38
FT /evidence="ECO:0007829|PDB:2HEO"
FT HELIX 42..54
FT /evidence="ECO:0007829|PDB:2HEO"
FT STRAND 57..62
FT /evidence="ECO:0007829|PDB:2HEO"
FT STRAND 65..68
FT /evidence="ECO:0007829|PDB:2HEO"
SQ SEQUENCE 411 AA; 44331 MW; 6D5F7B526A7DAA40 CRC64;
MAEAPVDLST GDNLEQKILQ VLSDDGGPVK IGQLVKKCQV PKKTLNQVLY RLKKEDRVSS
PEPATWSIGG AASGDGAPAI PENSSAQPSL DERILRFLEA NGPHRALHIA KALGMTTAKE
VNPLLYSMRN KHLLSYDGQT WKIYHSRQEG QDIAHSGVTQ ESPAIICQHN PVNMICQQGA
NSHISIANSN AIQIGHGNVI VREKACGEPG PRTSHPLPLA WDASAQDMPP VAHGAQYIYM
DKSLLQQVQL GHHNEMSLVG DAGKHPSYSF SDSPPEVSTT TADPGASFNM QTFEPGPHPE
GDTVQTVHIK SCFLEDATIG NGNKMTIHLR SKGEVMESGD SEEPKKEDTG TSSEATPPRS
CQHTPSDSML PTSELRAMAL GDSSPQTTEP VLREHEVQDI ESSQDTGLSK Q
