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 24-JAN-2024, entry version 198. 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 GN {ECO:0000303|PubMed:10231032}, 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 ACTIVITY REGULATION. RX PubMed=35165443; DOI=10.1038/s41589-021-00964-7; RA Rao S.D., Chen Q., Wang Q., Orth-He E.L., Saoi M., Griswold A.R., RA Bhattacharjee A., Ball D.P., Huang H.C., Chui A.J., Covelli D.J., You S., RA Cross J.R., Bachovchin D.A.; RT "M24B aminopeptidase inhibitors selectively activate the CARD8 RT inflammasome."; RL Nat. Chem. Biol. 18:565-574(2022). RN [28] RP FUNCTION, AND ACTIVITY REGULATION. RX PubMed=36357533; DOI=10.1038/s41589-022-01182-5; RA Clark K.M., Kim J.G., Wang Q., Gao H., Presti R.M., Shan L.; RT "Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1- RT infected cells."; RL Nat. Chem. Biol. 0:0-0(2022). RN [29] 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 [30] {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 [31] {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 [32] {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 [33] 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 [34] 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 [35] 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 [36] 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 [37] 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, PubMed:36357533). CC Inflammasomes are supramolecular complexes that assemble in the cytosol CC in response to pathogens and other damage-associated signals and play CC critical roles in innate immunity and inflammation (PubMed:11821383, CC PubMed:11408476, PubMed:15030775, PubMed:36357533). Acts as a CC recognition receptor (PRR): recognizes specific pathogens and other CC damage-associated signals, such as HIV-1 protease activity or Val- CC boroPro inhibitor, and mediates CARD8 inflammasome activation CC (PubMed:32840892, PubMed:33542150, PubMed:36357533). In response to CC pathogen-associated signals, the N-terminal part of CARD8 is degraded CC by the proteasome, releasing the cleaved C-terminal part of the protein CC (Caspase recruitment domain-containing protein 8, C-terminus), which CC polymerizes to initiate the formation of the inflammasome complex: the CC CARD8 inflammasome directly recruits pro-caspase-1 (proCASP1) CC independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, CC which subsequently cleaves and activates inflammatory cytokines IL1B CC and IL18 and gasdermin-D (GSDMD), leading to pyroptosis CC (PubMed:33053349, PubMed:32840892, PubMed:32051255, PubMed:33542150, CC PubMed:36357533). 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, ECO:0000269|PubMed:36357533}. 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 PubMed:36357533). Val-boroPro relieves inhibition of DPP8 and/or DPP9 CC by inducing the proteasome-mediated destruction of the N-terminal part CC of CARD8, releasing its C-terminal part from autoinhibition CC (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:34019797, CC PubMed:36357533). Indirectly activated by the pseudodipeptide CQ31 CC (PubMed:35165443). CQ31 directly inactivates the peptidases PEPD and CC XPNPEP1, leading to an accumulation of dipeptides that weaky inhibit CC DDP8 and DPP9, relieving DPP8- and/or DPP9-mediated inhibition of CARD8 CC (PubMed:35165443). {ECO:0000269|PubMed:29967349, CC ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:32796818, CC ECO:0000269|PubMed:32840892, ECO:0000269|PubMed:33053349, CC ECO:0000269|PubMed:33542150, ECO:0000269|PubMed:34019797, CC ECO:0000269|PubMed:35165443, ECO:0000269|PubMed:36357533}. 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="https://atlasgeneticsoncology.org/gene/913/CARD8"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. 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. DR RefSeq; XP_006723169.1; XM_006723106.3. DR RefSeq; XP_006723172.1; XM_006723109.3. DR RefSeq; XP_006723173.1; XM_006723110.3. 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. 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. 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 EMDB; EMD-22219; -. DR EMDB; EMD-22367; -. DR EMDB; EMD-22402; -. DR EMDB; EMD-9948; -. DR SMR; Q9Y2G2; -. DR BioGRID; 116564; 51. DR CORUM; Q9Y2G2; -. DR IntAct; Q9Y2G2; 39. DR MINT; Q9Y2G2; -. DR STRING; 9606.ENSP00000499211; -. 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; 9606-ENSP00000375767; -. DR PeptideAtlas; 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; 340 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 AGR; HGNC:17057; -. 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; DKSANRY; -. DR OrthoDB; 338452at2759; -. 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 1158 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 173 other cell types or tissues. DR ExpressionAtlas; Q9Y2G2; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; TAS:Reactome. 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:0140693; F:molecular condensate scaffold activity; IDA:UniProt. 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:0140374; P:antiviral innate immune response; IDA:UniProtKB. DR GO; GO:0140633; P:CARD8 inflammasome complex assembly; IDA:UniProt. DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB. DR GO; GO:0097340; P:inhibition of cysteine-type endopeptidase activity; IDA:UniProtKB. DR GO; GO:0043124; P:negative regulation of canonical NF-kappaB signal transduction; 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:0042981; P:regulation of apoptotic process; IEA:InterPro. DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IBA:GO_Central. DR GO; GO:0097264; P:self proteolysis; IDA:UniProtKB. DR CDD; cd01671; CARD; 1. DR Gene3D; 1.10.533.10; Death Domain, Fas; 1. DR InterPro; IPR001315; CARD. DR InterPro; IPR011029; DEATH-like_dom_sf. DR InterPro; IPR025307; FIIND_dom. DR PANTHER; PTHR46985:SF4; CASPASE RECRUITMENT DOMAIN-CONTAINING PROTEIN 8; 1. DR PANTHER; PTHR46985; NACHT, LRR AND PYD DOMAINS-CONTAINING PROTEIN 1; 1. DR Pfam; PF00619; CARD; 1. DR Pfam; PF13553; FIIND; 1. DR SUPFAM; SSF47986; DEATH domain; 1. DR PROSITE; PS50209; CARD; 1. DR PROSITE; PS51830; FIIND; 1. DR Genevisible; Q9Y2G2; HS. 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; uncertain 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 //