CARD8

The protein encoded by this gene belongs to the caspase recruitment domain (CARD)-containing family of proteins, which are involved in pathways leading to activation of caspases or nuclear factor kappa-B (NFKB). This protein may be a component of the inflammasome, a protein complex that plays a role in the activation of proinflammatory caspases. It is thought that this protein acts as an adaptor molecule that negatively regulates NFKB activation, CASP1-dependent IL1B secretion, and apoptosis. Polymorphisms in this gene may be associated with a susceptibility to rheumatoid arthritis. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2010]

Caspase Recruitment Domain Family Member 8

Inflammasome sensor, which mediates inflammasome activation in response to various pathogen-associated signals, leading to subsequent pyroptosis of CD4+ T-cells and macrophages (PubMed:11821383, PubMed:11408476, PubMed:15030775, PubMed:32840892, PubMed:32051255, PubMed:33542150).
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:11821383, PubMed:11408476, PubMed:15030775).
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).
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:33053349, PubMed:32840892, PubMed:32051255, PubMed:33542150).
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).
Caspase recruitment domain-containing protein 8: Constitutes the precusor 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.
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).
Caspase recruitment domain-containing protein 8, C-terminus: Constitutes the active part of the CARD8 inflammasome (PubMed:32840892).
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).

Activation of cysteine-type endopeptidase activity involved in apoptotic process Source: GO_Central
Inhibition of cysteine-type endopeptidase activity Source: UniProtKB
Negative regulation of I-kappaB kinase/NF-kappaB signaling Source: HGNC-UCL
Negative regulation of interleukin-1 beta production Source: UniProtKB
Negative regulation of lipopolysaccharide-mediated signaling pathway Source: UniProtKB
Negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
Negative regulation of tumor necrosis factor-mediated signaling pathway Source: UniProtKB
Positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
Positive regulation of interleukin-1 beta production Source: HGNC-UCL
Regulation of apoptotic process Source: InterPro
Regulation of I-kappaB kinase/NF-kappaB signaling Source: GO_Central

Nucleus; Cytoplasm
Caspase recruitment domain-containing protein 8, C-terminus: Inflammasome

Inflammatory bowel disease 30 (IBD30): 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).
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.

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.
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.
(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.
Isoform 1: Undergoes less autocatalytic processing within the FIIND domain compared to isoform 5.