| IED ID | IndEnz0002004467 |
| Enzyme Type ID | protease004467 |
| Protein Name |
Caspase-4 CASP-4 EC 3.4.22.57 ICE and Ced-3 homolog 2 ICH-2 ICE rel -II Mih1 Protease TX Cleaved into: Caspase-4 subunit p10; Caspase-4 subunit p20 |
| Gene Name | CASP4 ICH2 |
| 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 | MAEGNHRKKPLKVLESLGKDFLTGVLDNLVEQNVLNWKEEEKKKYYDAKTEDKVRVMADSMQEKQRMAGQMLLQTFFNIDQISPNKKAHPNMEAGPPESGESTDALKLCPHEEFLRLCKERAEEIYPIKERNNRTRLALIICNTEFDHLPPRNGADFDITGMKELLEGLDYSVDVEENLTARDMESALRAFATRPEHKSSDSTFLVLMSHGILEGICGTVHDEKKPDVLLYDTIFQIFNNRNCLSLKDKPKVIIVQACRGANRGELWVRDSPASLEVASSQSSENLEEDAVYKTHVEKDFIAFCSSTPHNVSWRDSTMGSIFITQLITCFQKYSWCCHLEEVFRKVQQSFETPRAKAQMPTIERLSMTRYFYLFPGN |
| Enzyme Length | 377 |
| Uniprot Accession Number | P49662 |
| Absorption | |
| Active Site | ACT_SITE 210; /evidence="ECO:0000250|UniProtKB:P29466"; ACT_SITE 258; /evidence="ECO:0000269|PubMed:22246630, ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:7743998" |
| Activity Regulation | ACTIVITY REGULATION: Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner (PubMed:25119034). {ECO:0000269|PubMed:25119034}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Strict requirement for Asp at the P1 position. It has a preferred cleavage sequence of Tyr-Val-Ala-Asp-|- but also cleaves at Asp-Glu-Val-Asp-|-.; EC=3.4.22.57; Evidence={ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:7797510}; |
| DNA Binding | |
| EC Number | 3.4.22.57 |
| Enzyme Function | FUNCTION: Inflammatory caspase that acts as an essential effector of the NLRP3 and NLRP6 inflammasomes by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:7797510, PubMed:23516580, PubMed:26375003, PubMed:32109412). Thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:7797510, PubMed:15326478, PubMed:23516580, PubMed:26375003, PubMed:28314590, PubMed:32109412). Required for innate immunity to cytosolic, but not vacuolar, bacteria (By similarity). Plays a key role in NLRP3-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation, cholera enterotoxin subunit B and cytosolic LPS (PubMed:26508369, PubMed:22246630, PubMed:23516580, PubMed:24879791, PubMed:25119034, PubMed:26173988, PubMed:26174085, PubMed:25964352). Activated by direct binding to LPS without the need of an upstream sensor (PubMed:25119034). Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, which leads to CASP1 activation and IL1B and IL18 secretion (PubMed:33377178). Independently of NLRP3 inflammasome and CASP1, promotes pyroptosis, through GSDMD cleavage and activation, followed by IL1A, IL18 and HMGB1 release in response to non-canonical inflammasome activators (PubMed:26375003, PubMed:32109412). Plays a crucial role in the restriction of Salmonella typhimurium replication in colonic epithelial cells during infection: in later stages of the infection, LPS from cytosolic Salmonella triggers CASP4 activation, which catalyzes cleavage of GSDMD, resulting in pyroptosis of infected cells and their extrusion into the gut lumen, as well as in IL18 secretion (PubMed:25121752, PubMed:26375003, PubMed:25964352, PubMed:34671164, PubMed:32109412). Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752, PubMed:26375003, PubMed:25964352). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains (PubMed:23661706, PubMed:15123740, PubMed:22246630). Catalyzes cleavage and maturation of IL18 (PubMed:15326478). In contrast, it does not directly process IL1B (PubMed:7743998, PubMed:7797592, PubMed:7797510). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590). {ECO:0000250|UniProtKB:P70343, ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:15326478, ECO:0000269|PubMed:22246630, ECO:0000269|PubMed:23516580, ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:25964352, ECO:0000269|PubMed:26173988, ECO:0000269|PubMed:26174085, ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:26508369, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:33377178, ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510, ECO:0000269|PubMed:7797592}.; FUNCTION: (Microbial infection) In response to the Td92 surface protein of the periodontal pathogen T.denticola, activated by cathepsin CTSG which leads to production and secretion of IL1A and pyroptosis of gingival fibroblasts. {ECO:0000269|PubMed:29077095}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (7); Beta strand (12); Chain (2); Domain (1); Erroneous gene model prediction (1); Erroneous translation (1); Frameshift (1); Helix (11); Initiator methionine (1); Modified residue (3); Mutagenesis (6); Natural variant (3); Propeptide (2); Region (2); Site (1); Turn (4) |
| Keywords | 3D-structure;Acetylation;Alternative splicing;Cytoplasm;Endoplasmic reticulum;Hydrolase;Immunity;Inflammasome;Inflammatory response;Innate immunity;Membrane;Mitochondrion;Necrosis;Phosphoprotein;Protease;Reference proteome;Secreted;Thiol protease;Zymogen |
| Interact With | |
| Induction | INDUCTION: In peripheral blood mononuclear cells and purified monocytes, up-regulated by bacterial lipopolysaccharides (LPS) and interferon-beta/IFNB1 at the mRNA level (PubMed:16893518, PubMed:24879791). However, this increase is not observed at the protein level, which remains constant in monocytes and other cell types following LPS treatment (PubMed:25121752) (PubMed:26508369). In monocyte-derived macrophages, some up-regulation at the protein level is observed following treatment with LPS and IFNB1 (PubMed:25964352). In SH-EP1 neuroblastoma cell line, up-regulated by NF-kappa-B RELA/p65 at both mRNA and protein levels. {ECO:0000269|PubMed:16893518, ECO:0000269|PubMed:24879791, ECO:0000269|PubMed:25695505}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000269|PubMed:23661706}. Endoplasmic reticulum membrane {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:23661706}; Peripheral membrane protein {ECO:0000269|PubMed:23661706}; Cytoplasmic side {ECO:0000269|PubMed:23661706}. Mitochondrion {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:23661706}. Inflammasome {ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:26508369}. Secreted {ECO:0000269|PubMed:22246630}. Note=Predominantly localizes to the endoplasmic reticulum (ER). Association with the ER membrane requires TMEM214 (PubMed:15123740). Released in the extracellular milieu by keratinocytes following UVB irradiation (PubMed:22246630). {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:22246630}. |
| Modified Residue | MOD_RES 83; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231"; MOD_RES 314; /note="(Microbial infection) ADP-riboxanated arginine"; /evidence="ECO:0000269|PubMed:34671164"; MOD_RES P49662-2:2; /note="N-acetylalanine"; /evidence="ECO:0007744|PubMed:22814378" |
| Post Translational Modification | PTM: In response to activation signals, including endoplasmic reticulum stress or treatment with amyloid-beta A4 protein fragments (such as amyloid-beta protein 40), undergoes autoproteolytic cleavage. {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:7743998, ECO:0000269|PubMed:7797510}.; PTM: (Microbial infection) ADP-riboxanation by S.flexneri OspC3 blocks CASP4 autoprocessing, preventing CASP4 activation and ability to recognize and cleave GSDMD, thereby thwarting the inflammasome/pyroptosis-mediated defense. {ECO:0000269|PubMed:34671164}. |
| Signal Peptide | |
| Structure 3D | X-ray crystallography (2) |
| Cross Reference PDB | 6KMZ; 6NRY; |
| Mapped Pubmed ID | 10329646; 12096920; 17353931; 19773279; 20711500; 21282934; 21988832; 29177860; 29891674; |
| Motif | |
| Gene Encoded By | |
| Mass | 43,262 |
| Kinetics | BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=681 uM for synthetic peptide acetyl-YVAD-p-nitroanilide {ECO:0000269|PubMed:7797510}; Note=Values obtained using the partial C-terminal enzyme sequence of 105-377. {ECO:0000269|PubMed:7797510}; |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.22.57; |