| IED ID | IndEnz0002014050 |
| Enzyme Type ID | protease014050 |
| Protein Name |
Caspase recruitment domain-containing protein 8 EC 3.4.-.- CARD-inhibitor of NF-kappa-B-activating ligand CARDINAL Tumor up-regulated CARD-containing antagonist of CASP9 TUCAN Cleaved into: Caspase recruitment domain-containing protein 8, C-terminus CARD8-CT ; Caspase recruitment domain-containing protein 8, N-terminus CARD8-NT |
| Gene Name | CARD8 DACAR KIAA0955 NDPP1 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MEKKECPEKSSSSEEELPRRDSGSSRNIDASKLIRLQGSRKLLVDNSIRELQYTKTGIFFQAEACVTNDTVYRELPCVSETLCDISHFFQEDDETEAEPLLFRAVPECQLSGGDIPSVSEEQESSEGQDSGDICSEENQIVSSYASKVCFEIEEDYKNRQFLGPEGNVDVELIDKSTNRYSVWFPTAGWYLWSATGLGFLVRDEVTVTIAFGSWSQHLALDLQHHEQWLVGGPLFDVTAEPEEAVAEIHLPHFISLQAGEVDVSWFLVAHFKNEGMVLEHPARVEPFYAVLESPSFSLMGILLRIASGTRLSIPITSNTLIYYHPHPEDIKFHLYLVPSDALLTKAIDDEEDRFHGVRLQTSPPMEPLNFGSSYIVSNSANLKVMPKELKLSYRSPGEIQHFSKFYAGQMKEPIQLEITEKRHGTLVWDTEVKPVDLQLVAASAPPPFSGAAFVKENHRQLQARMGDLKGVLDDLQDNEVLTENEKELVEQEKTRQSKNEALLSMVEKKGDLALDVLFRSISERDPYLVSYLRQQNL |
| Enzyme Length | 537 |
| Uniprot Accession Number | Q9Y2G2 |
| Absorption | |
| Active Site | |
| 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: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). {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}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | 3.4.-.- |
| Enzyme 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: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). {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}.; 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}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (7); Beta strand (1); Chain (3); Compositional bias (2); Domain (2); Erroneous initiation (1); Helix (8); Mutagenesis (36); Natural variant (5); Region (4); Sequence conflict (9); Site (2) |
| Keywords | 3D-structure;Alternative splicing;Cytoplasm;Direct protein sequencing;Disease variant;Host-virus interaction;Hydrolase;Immunity;Inflammasome;Inflammatory response;Innate immunity;Necrosis;Nucleus;Protease;Reference proteome;Ubl conjugation |
| Interact With | |
| Induction | |
| 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}. |
| Modified Residue | |
| 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}. |
| Signal Peptide | |
| Structure 3D | Electron microscopy (4); X-ray crystallography (1) |
| Cross Reference PDB | 4IKM; 6K9F; 6XKJ; 7JKQ; 7JN7; |
| Mapped Pubmed ID | 16796750; 17484912; 17595233; 17878386; 18092344; 18263599; 18311798; 18841008; 19074885; 19252766; 19443463; 19664744; 19843337; 19940360; 20182451; 20379614; 20453000; 20711500; 20800603; 21248762; 21308686; 21621776; 22128899; 22227487; 23053059; 23088220; 23507658; 23547871; 23563199; 23611467; 24098386; 24385277; 25313070; 25564880; 25790751; 25895569; 25921775; 26283210; 26462562; 27110561; 27550484; 27697150; 27810076; 28135700; 28137891; 28185410; 29097263; 29230505; 30088494; 30211233; 30816317; 31529732; 32080163; 32104685; 32396255; 32613553; 32689633; 33067783; 33164551; 34587665; 9390557; |
| Motif | |
| Gene Encoded By | |
| Mass | 60,652 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |