CARD8
entrez
22900
canonical
uniprot
Q9Y2G2
canonical
ensembl
ENSG00000105483
resolver
ensp
ENSP00000391248
resolver
ensp
ENSP00000428736
resolver
ensp
ENSP00000428883
resolver
ensp
ENSP00000429839
resolver
ensp
ENSP00000430108
resolver
ensp
ENSP00000430747
resolver
ensp
ENSP00000499211
resolver
ensp
ENSP00000547837
resolver
ensp
ENSP00000675598
resolver
genesymbol
CARD8
resolver
genesymbol_syn
DACAR
resolver
genesymbol_syn
KIAA0955
resolver
genesymbol_syn
NDPP1
resolver
hgnc
HGNC:17057
resolver
uniprot
B5KVR6
resolver
uniprot
B5KVR8
resolver
uniprot
B7Z496
resolver
uniprot
B7Z4A2
resolver
uniprot
E5RFV9
resolver
uniprot
E9PEM7
resolver
uniprot
G3XAM9
resolver
uniprot
Q6PGP8
resolver
uniprot
Q96P82
resolver
uniprot_entry
CARD8_HUMAN
resolver
uniprot_sec
B5KVR6
resolver
uniprot_sec
B5KVR8
resolver
uniprot_sec
B7Z496
resolver
uniprot_sec
B7Z4A2
resolver
uniprot_sec
E5RFV9
resolver
uniprot_sec
E9PEM7
resolver
uniprot_sec
G3XAM9
resolver
uniprot_sec
Q6PGP8
resolver
uniprot_sec
Q96P82
resolver
activity_regulation
ACTIVITY REGULATION: CARD8 inflammasome is activated by HIV-1 protease activity: HIV-1 protease cleaves CARD8, promoting ubiquitination and degradation of the N-terminal part, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes and forms the CARD8 inflammasome (PubMed:33542150). CARD8 inflammasome is inhibited by DPP8 and DPP9, which sequester the C-terminal fragment of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) in a ternary complex, thereby preventing CARD8 oligomerization and activation (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:34019797). CARD8 inflammasome is activated by Val-boroPro (Talabostat, PT-100), an inhibitor of dipeptidyl peptidases DPP8 and DPP9 (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:32840892, PubMed:33053349, PubMed:34019797, PubMed:36357533). Val-boroPro relieves inhibition of DPP8 and/or DPP9 by inducing the proteasome-mediated destruction of the N-terminal part of CARD8, releasing its C-terminal part from autoinhibition (PubMed:29967349, PubMed:31525884, PubMed:32796818, PubMed:34019797, PubMed:36357533). Indirectly activated by the pseudodipeptide CQ31 (PubMed:35165443). CQ31 directly inactivates the peptidases PEPD and XPNPEP1, leading to an accumulation of dipeptides that weakly inhibit DDP8 and DPP9, relieving DPP8- and/or DPP9-mediated inhibition of CARD8 (PubMed:35165443). {ECO:0000269|PubMed:29967349, ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:32796818, ECO:0000269|PubMed:32840892, ECO:0000269|PubMed:33053349, ECO:0000269|PubMed:33542150, ECO:0000269|PubMed:34019797, ECO:0000269|PubMed:35165443, ECO:0000269|PubMed:36357533}.
uniprot
proteins
amino_acid_sequence
MEKKECPEKSSSSEEELPRRDSGSSRNIDASKLIRLQGSRKLLVDNSIRELQYTKTGIFFQAEACVTNDTVYRELPCVSETLCDISHFFQEDDETEAEPLLFRAVPECQLSGGDIPSVSEEQESSEGQDSGDICSEENQIVSSYASKVCFEIEEDYKNRQFLGPEGNVDVELIDKSTNRYSVWFPTAGWYLWSATGLGFLVRDEVTVTIAFGSWSQHLALDLQHHEQWLVGGPLFDVTAEPEEAVAEIHLPHFISLQAGEVDVSWFLVAHFKNEGMVLEHPARVEPFYAVLESPSFSLMGILLRIASGTRLSIPITSNTLIYYHPHPEDIKFHLYLVPSDALLTKAIDDEEDRFHGVRLQTSPPMEPLNFGSSYIVSNSANLKVMPKELKLSYRSPGEIQHFSKFYAGQMKEPIQLEITEKRHGTLVWDTEVKPVDLQLVAASAPPPFSGAAFVKENHRQLQARMGDLKGVLDDLQDNEVLTENEKELVEQEKTRQSKNEALLSMVEKKGDLALDVLFRSISERDPYLVSYLRQQNL
uniprot
proteins
disease_involvement
DISEASE: Inflammatory bowel disease 30 (IBD30) [MIM:619079]: A chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology and a multifactorial inheritance pattern. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints. {ECO:0000269|PubMed:17030188, ECO:0000269|PubMed:19319132, ECO:0000269|PubMed:23506543, ECO:0000269|PubMed:26462578, ECO:0000269|PubMed:29408806}. Note=The disease may be caused by variants affecting the gene represented in this entry. A number of groups have studied the possible association between variant rs2043211 and inflammatory bowel disease (PubMed:17030188, PubMed:19319132, PubMed:23506543, PubMed:26462578). According to some studies involving a limited number of patients, this variant is associated with inflammatory bowel disease (PubMed:17030188, PubMed:19319132, PubMed:23506543). Such association is however not confirmed in studies involving a large number of patients (PubMed:26462578). Discrepancies between studies may be caused by the variable consequences of this polymorphism in the different isoforms (PubMed:29408806). Whereas rs2043211 introduces a stop codon after 'Cys-10' (Cys10Ter) in isoform 1, and therefore the likely formation of a downstream transcriptional start site for this isoform, it causes Ile-102 variation in isoform 5, due to the upstream start site (PubMed:29408806). Moreover, most patients bearing this polymorphism continue to express the slightly smaller but fully functional isoform 7, as a result of transcription downstream of the rs2043211 polymorphism (PubMed:29408806). {ECO:0000269|PubMed:17030188, ECO:0000269|PubMed:19319132, ECO:0000269|PubMed:23506543, ECO:0000269|PubMed:26462578, ECO:0000269|PubMed:29408806}.
uniprot
proteins
ec_number
3.4.-.-
uniprot
proteins
function
FUNCTION: Inflammasome sensor, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis of CD4(+) T-cells and macrophages (PubMed:11408476, PubMed:11821383, PubMed:15030775, PubMed:32051255, PubMed:32840892, PubMed:33542150, PubMed:34019797, PubMed:36357533). Inflammasomes are supramolecular complexes that assemble in the cytosol in response to pathogens and other damage-associated signals and play critical roles in innate immunity and inflammation (PubMed:11408476, PubMed:11821383, PubMed:15030775, PubMed:36357533). Acts as a recognition receptor (PRR): recognizes specific pathogens and other damage-associated signals, such as HIV-1 protease activity or Val-boroPro inhibitor, and mediates CARD8 inflammasome activation (PubMed:32840892, PubMed:33542150, PubMed:36357533). In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes to initiate the formation of the inflammasome complex: the CARD8 inflammasome directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC and promotes caspase-1 (CASP1) activation, which subsequently cleaves and activates inflammatory cytokines IL1B and IL18 and gasdermin-D (GSDMD), leading to pyroptosis (PubMed:32051255, PubMed:32840892, PubMed:33053349, PubMed:33542150, PubMed:36357533). Ability to sense HIV-1 protease activity leads to the clearance of latent HIV-1 in patient CD4(+) T-cells after viral reactivation; in contrast, HIV-1 can evade CARD8-sensing when its protease remains inactive in infected cells prior to viral budding (PubMed:33542150). Also acts as a negative regulator of the NLRP3 inflammasome (PubMed:24517500). May also act as an inhibitor of NF-kappa-B activation (PubMed:11551959, PubMed:12067710). {ECO:0000269|PubMed:11408476, ECO:0000269|PubMed:11551959, ECO:0000269|PubMed:11821383, ECO:0000269|PubMed:12067710, ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:24517500, ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:32840892, ECO:0000269|PubMed:33053349, ECO:0000269|PubMed:33542150, ECO:0000269|PubMed:34019797, ECO:0000269|PubMed:36357533}.; FUNCTION: [Caspase recruitment domain-containing protein 8]: Constitutes the precursor of the CARD8 inflammasome, which mediates autoproteolytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals. {ECO:0000269|PubMed:22087307}.; FUNCTION: [Caspase recruitment domain-containing protein 8, N-terminus]: Regulatory part that prevents formation of the CARD8 inflammasome: in absence of pathogens and other damage-associated signals, interacts with the C-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus), preventing activation of the CARD8 inflammasome (PubMed:33542150). In response to pathogen-associated signals, this part is ubiquitinated by the N-end rule pathway and degraded by the proteasome, releasing the cleaved C-terminal part of the protein, which polymerizes and forms the CARD8 inflammasome (Probable) (PubMed:32558991). {ECO:0000269|PubMed:33542150, ECO:0000303|PubMed:32558991, ECO:0000305|PubMed:33053349}.; FUNCTION: [Caspase recruitment domain-containing protein 8, C-terminus]: Constitutes the active part of the CARD8 inflammasome (PubMed:32840892, PubMed:34019797). In absence of pathogens and other damage-associated signals, interacts with the N-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, N-terminus), preventing activation of the CARD8 inflammasome (PubMed:33542150). In response to pathogen-associated signals, the N-terminal part of CARD8 is degraded by the proteasome, releasing this form, which polymerizes to form the CARD8 inflammasome complex: the CARD8 inflammasome complex then directly recruits pro-caspase-1 (proCASP1) and promotes caspase-1 (CASP1) activation, leading to gasdermin-D (GSDMD) cleavage and subsequent pyroptosis (PubMed:32840892, PubMed:33542150). {ECO:0000269|PubMed:32840892, ECO:0000269|PubMed:33542150, ECO:0000269|PubMed:34019797}.
uniprot
proteins
mass_dalton
60652
uniprot
proteins
mutagenesis
MUTAGEN 51; /note="L->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 52; /note="Q->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 53; /note="Y->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 54; /note="T->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 55; /note="K->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 56; /note="T->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 57; /note="G->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 58; /note="I->A: Does not affect cleavage by HIV-1 protease."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 59; /note="F->A: Abolished cleavage by HIV-1 protease, leading to prevent formation of the CARD8 inflammasome and subsequent pyroptosis."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 60; /note="F->A: Abolished cleavage by HIV-1 protease, leading to prevent formation of the CARD8 inflammasome and subsequent pyroptosis."; /evidence="ECO:0000269|PubMed:33542150"; MUTAGEN 157; /note="K->R: Does not affect sensitivity to Val-boroPro."; /evidence="ECO:0000269|PubMed:33053349"; MUTAGEN 240; /note="E->A: No effect on autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 242; /note="E->A: No effect on autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 252; /note="H->A: Severe loss of autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 270; /note="H->A: Severe loss of autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 274; /note="E->R: Abolished interaction with DPP9, without affecting autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:34019797"; MUTAGEN 279; /note="E->A: Partial loss of autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 280; /note="H->A: No effect on autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 295; /note="S->A: Partial loss of autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 295; /note="S->Q: No effect on autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 296; /note="F->H: Severe loss of autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 297; /note="S->A: Complete loss of autocatalytic cleavage. Abolished ability to form the CARD8 inflammasome and trigger pyroptosis. Abolished sensitivity to Val-boroPro. Does not affect interaction with DPP9."; /evidence="ECO:0000269|PubMed:22087307, ECO:0000269|PubMed:29967349, ECO:0000269|PubMed:31525884, ECO:0000269|PubMed:32051255, ECO:0000269|PubMed:33542150, ECO:0000269|PubMed:34019797"; MUTAGEN 333; /note="H->A: No effect on autocatalytic cleavage."; /evidence="ECO:0000269|PubMed:22087307"; MUTAGEN 368; /note="L->G: Does not affect autocatalytic cleavage; does not affect interaction with DPP9; impaired interaction with the C-terminal fragment of CARD8 in the ternary complex."; /evidence="ECO:0000269|PubMed:34019797"; MUTAGEN 370; /note="F->G: Does not affect autocatalytic cleavage; does not affect interaction with DPP9; impaired interaction with the C-terminal fragment of CARD8 in the ternary complex."; /evidence="ECO:0000269|PubMed:34019797"; MUTAGEN 394; /note="R->E: Does not affect autocatalytic cleavage; does not affect interaction with DPP9; impaired interaction with the C-terminal fragment of CARD8 in the ternary complex."; /evidence="ECO:0000269|PubMed:34019797"; MUTAGEN 405; /note="F->G: Does not affect autocatalytic cleavage; does not affect interaction with DPP9; impaired interaction with the C-terminal fragment of CARD8 in the ternary complex."; /evidence="ECO:0000269|PubMed:34019797"; MUTAGEN 459; /note="R->E: Abolished formation of inflammasome filaments. Abolished ability to induce pyroptosis."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN 464; /note="R->E: Abolished formation of inflammasome filaments. Abolished ability to induce pyroptosis."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN 472; /note="L->R: Inhibits homodimer formation."; /evidence="ECO:0000269|PubMed:12067710"; MUTAGEN 485; /note="E->R: Abolished formation of inflammasome filaments. Abolished ability to induce pyroptosis."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN 490; /note="E->R: Abolished formation of inflammasome filaments."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN 495; /note="R->E: Abolished formation of inflammasome filaments. Abolished ability to induce pyroptosis."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN 511; /note="D->K: Abolished formation of inflammasome filaments. Reduced ability to induce pyroptosis."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN 527; /note="Y->A: Abolished formation of inflammasome filaments. Abolished ability to induce pyroptosis."; /evidence="ECO:0000269|PubMed:33420033"; MUTAGEN Q9Y2G2-1:152; /note="Q->QA: Increased autocalalytic cleavage."; /evidence="ECO:0000269|PubMed:33053349
uniprot
proteins
post_translational_modification
PTM: [Caspase recruitment domain-containing protein 8]: Undergoes autocatalytic processing within the FIIND domain to generate the N-terminal and C-terminal parts, which are associated non-covalently in absence of pathogens and other damage-associated signals. {ECO:0000269|PubMed:22087307, ECO:0000269|PubMed:33542150}.; PTM: [Caspase recruitment domain-containing protein 8, N-terminus]: Ubiquitinated by the N-end rule pathway in response to pathogens and other damage-associated signals, leading to its degradation by the proteasome and subsequent release of the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes and forms the CARD8 inflammasome. {ECO:0000303|PubMed:32558991, ECO:0000305|PubMed:33053349}.; PTM: (Microbial infection) Proteolytic cleavage by HIV-1 protease in the disordered region and within the ZU5 region of the FIIND domain promotes ubiquitination of the N-terminal part by the N-end rule pathway and degradation by the proteasome, releasing the cleaved C-terminal part of the protein (Caspase recruitment domain-containing protein 8, C-terminus), which polymerizes and forms the CARD8 inflammasome. {ECO:0000269|PubMed:33542150}.; PTM: [Isoform 1]: Undergoes less autocatalytic processing within the FIIND domain compared to isoform 5. {ECO:0000269|PubMed:33053349}.
uniprot
proteins
pubmed
10231032
uniprot
proteins
pubmed
11408476
uniprot
proteins
pubmed
11551959
uniprot
proteins
pubmed
11821383
uniprot
proteins
pubmed
11956601
uniprot
proteins
pubmed
12067710
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15030775
uniprot
proteins
pubmed
15057824
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
17030188
uniprot
proteins
pubmed
18212821
uniprot
proteins
pubmed
19319132
uniprot
proteins
pubmed
22087307
uniprot
proteins
pubmed
23506543
uniprot
proteins
pubmed
23695559
uniprot
proteins
pubmed
24517500
uniprot
proteins
pubmed
26462578
uniprot
proteins
pubmed
29408806
uniprot
proteins
pubmed
29967349
uniprot
proteins
pubmed
31525884
uniprot
proteins
pubmed
32051255
uniprot
proteins
pubmed
32558991
uniprot
proteins
pubmed
32796818
uniprot
proteins
pubmed
32840892
uniprot
proteins
pubmed
33053349
uniprot
proteins
pubmed
33154409
uniprot
proteins
pubmed
33420028
uniprot
proteins
pubmed
33420033
uniprot
proteins
pubmed
33542150
uniprot
proteins
pubmed
33731929
uniprot
proteins
pubmed
34019797
uniprot
proteins
pubmed
35165443
uniprot
proteins
pubmed
36357533
uniprot
proteins
sequence_length
537
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:24517500, ECO:0000269|PubMed:33154409}. Nucleus {ECO:0000269|PubMed:15030775, ECO:0000269|PubMed:33154409}.; SUBCELLULAR LOCATION: [Caspase recruitment domain-containing protein 8, C-terminus]: Inflammasome {ECO:0000269|PubMed:32840892, ECO:0000269|PubMed:33420028, ECO:0000269|PubMed:33420033, ECO:0000269|PubMed:33542150}.
uniprot
proteins