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, PubMed:34019797). 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). 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. 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). 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). 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:33053349, PubMed:32840892, PubMed:34019797). 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). Interacts with DPP9; leading to inhibit activation of the inflammasome (PubMed:31525884, PubMed:33731929, PubMed:34019797). DPP9 acts via formation of a ternary complex, composed of a DPP9 homodimer, one full-length CARD8 protein, and one cleaved C-terminus of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) (PubMed:34019797). Interacts with DPP8; leading to inhibit activation of the inflammasome, probably via formation of a ternary complex with DPP8 (PubMed:31525884). Interacts with NLRP3 (PubMed:24517500). Interacts with IKBKG/NEMO (PubMed:11551959). Interacts with DRAL (PubMed:12067710). Binds to caspase-1 (CASP1), CARD16/pseudo-ICE and CARD18/ICEBERG (PubMed:11821383). Interacts with NLRP2 (via NACHT domain) (PubMed:15030775). Interacts with the C-terminal part of CARD8 (Caspase recruitment domain-containing protein 8, C-terminus) 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) in absence of pathogens and other damage-associated signals (PubMed:33542150). Homomultimer; forms the CARD8 inflammasome polymeric complex, a filament composed of homopolymers of this form in response to pathogens and other damage-associated signals (PubMed:33420028, PubMed:33420033). The CARD8 inflammasome polymeric complex directly recruits pro-caspase-1 (proCASP1) independently of PYCARD/ASC (PubMed:32051255). Interacts (via CARD domain) with CASP1 (via CARD domain); leading to CASP1 activation (PubMed:33542150, PubMed:33420033). High expression in lung, ovary, testis and placenta (PubMed:11551959). Lower expression in heart, kidney and liver (PubMed:11551959). Also expressed in spleen, lymph node and bone marrow (PubMed:11821383). The disordered region is required for activation of the CARD8 inflammasome. The C-terminal part of CARD8 oligomerizes to form the core of the CARD8 inflammasome filament: in the filament, the CARD domains form a central helical filaments that are promoted by oligomerized, but flexibly linked, UPA regions surrounding the filaments (PubMed:33420028, PubMed:33420033). The UPA region reduces the threshold needed for filament formation and signaling (PubMed:33420028, PubMed:33420033). Directly recruits and polymerizes with the CARD domain of caspase-1 (CASP1) through the favorable side of the growing filament seed (PubMed:33420033). 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. 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. Undergoes less autocatalytic processing within the FIIND domain compared to isoform 5. 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). Extended N-terminus.