| IED ID | IndEnz0002005973 |
| Enzyme Type ID | protease005973 |
| Protein Name |
Caspase-4 CASP-4 EC 3.4.22.64 Caspase-11 CASP-11 Protease ICH-3 Cleaved into: Caspase-4 subunit p10; Caspase-4 subunit p20 |
| Gene Name | Casp4 Casp11 Caspl Ich3 |
| Organism | Mus musculus (Mouse) |
| 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 Glires (Rodents and rabbits) Rodentia Myomorpha (mice and others) Muroidea Muridae Murinae Mus Mus Mus musculus (Mouse) |
| Enzyme Sequence | MAENKHPDKPLKVLEQLGKEVLTEYLEKLVQSNVLKLKEEDKQKFNNAERSDKRWVFVDAMKKKHSKVGEMLLQTFFSVDPGSHHGEANLEMEEPEESLNTLKLCSPEEFTRLCREKTQEIYPIKEANGRTRKALIICNTEFKHLSLRYGANFDIIGMKGLLEDLGYDVVVKEELTAEGMESEMKDFAALSEHQTSDSTFLVLMSHGTLHGICGTMHSEKTPDVLQYDTIYQIFNNCHCPGLRDKPKVIIVQACRGGNSGEMWIRESSKPQLCRGVDLPRNMEADAVKLSHVEKDFIAFYSTTPHHLSYRDKTGGSYFITRLISCFRKHACSCHLFDIFLKVQQSFEKASIHSQMPTIDRATLTRYFYLFPGN |
| Enzyme Length | 373 |
| Uniprot Accession Number | P70343 |
| Absorption | |
| Active Site | ACT_SITE 206; /evidence=ECO:0000250|UniProtKB:P29466; ACT_SITE 254; /evidence=ECO:0000250|UniProtKB:P49662 |
| Activity Regulation | ACTIVITY REGULATION: Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner. {ECO:0000269|PubMed:25119034}. |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Strict requirement for Asp at the P1 position and has a preferred cleavage sequence of (Ile/Leu/Val/Phe)-Gly-His-Asp-|-.; EC=3.4.22.64; Evidence={ECO:0000250|UniProtKB:P49662}; |
| DNA Binding | |
| EC Number | 3.4.22.64 |
| Enzyme Function | FUNCTION: Inflammatory caspase that acts as an essential effector of the NLRP3 and NLRP6 inflammasomes by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:23348507, PubMed:30392956). Thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:26375003, PubMed:30392956). Required for innate immunity to cytosolic, but not vacuolar, bacteria (PubMed:23348507). 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:8702803, PubMed:9038361, PubMed:22002608, PubMed:25119034). 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:30392956). 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:22002608, PubMed:23348507, PubMed:26320999, PubMed:26375003). 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:34671164). 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, PubMed:32554464). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (By similarity). Catalyzes cleavage and maturation of IL18 (By similarity). In contrast, it does not directly process IL1B (PubMed:8702803, PubMed:9038361). 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:P49662, ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:23348507, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:26320999, ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:30392956, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32554464, ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:8702803, ECO:0000269|PubMed:9038361}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (2); Beta strand (15); Chain (2); Domain (1); Helix (10); Modified residue (2); Mutagenesis (15); Propeptide (2); Region (1); Sequence conflict (2); Turn (4) |
| Keywords | 3D-structure;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: Up-regulated by LPS and E.coli (PubMed:8702803, PubMed:10986288, PubMed:22002608, PubMed:26375259). In LPS-induced lung inflammation, markedly up-regulated after 6 hours of treatment and decreases at 24 hours. The induction is dependent upon DDIT3/CHOP-mediated ER stress (at protein level) (PubMed:16670335). In the spleen and in bone marrow-derived macrophages, up-regulated by poly(I:C), a synthetic analog of double-stranded RNA (at protein level) (PubMed:26320999, PubMed:26375259). Also induced by IFNG and interferon-alpha. Up-regulated by R848, a TLR7 synthetic activator, and Pam3CysK4, a synthetic activator of TLR1/TLR2 (PubMed:26375259). {ECO:0000269|PubMed:10986288, ECO:0000269|PubMed:16670335, ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:26320999, ECO:0000269|PubMed:26375259, ECO:0000269|PubMed:8702803}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250|UniProtKB:P49662}. Cytoplasm {ECO:0000269|PubMed:16670335}. Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P49662}; Peripheral membrane protein {ECO:0000250|UniProtKB:P49662}; Cytoplasmic side {ECO:0000250|UniProtKB:P49662}. Mitochondrion {ECO:0000250|UniProtKB:P49662}. Inflammasome {ECO:0000269|PubMed:25119034}. Secreted {ECO:0000250|UniProtKB:P49662}. Note=Predominantly localizes to the endoplasmic reticulum (ER). Association with the ER membrane requires TMEM214. Released in the extracellular milieu by keratinocytes following UVB irradiation. {ECO:0000250|UniProtKB:P49662}. |
| Modified Residue | MOD_RES 83; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:P49662; MOD_RES 310; /note=(Microbial infection) ADP-riboxanated arginine; /evidence=ECO:0000269|PubMed:34671164 |
| Post Translational Modification | PTM: In response to activation signals, including cholera enterotoxin subunit B, infection by E. coli or S. typhimurium or endoplasmic reticulum stress, undergoes autoproteolytic cleavage. {ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:30392956, ECO:0000269|PubMed:32109412}.; 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 (5) |
| Cross Reference PDB | 6KMT; 6KMU; 6KMV; 6KN1; 6NS7; |
| Mapped Pubmed ID | 10087912; 10101687; 10222134; 10377054; 10403638; 10618441; 10671365; 10739653; 10974017; 11136825; 11217851; 11526440; 11536012; 11902113; 12198138; 12232800; 12466851; 12480175; 12819136; 12843244; 14985426; 15383538; 15545923; 15880263; 16380090; 17293856; 17963913; 18003616; 18309324; 18411310; 18474237; 19531658; 19695249; 19801895; 21267068; 21269505; 21386911; 21530491; 21677750; 21720866; 22332634; 22365665; 22658523; 22753929; 22819539; 22895188; 22898816; 22911706; 23144495; 23219391; 23226472; 23307811; 23645208; 23762026; 23870309; 24037676; 24093676; 24194600; 24312444; 24453255; 24630989; 24638169; 24715728; 24739961; 24850431; 24875775; 24879791; 25162221; 25198773; 25347553; 25367751; 25414099; 25548224; 25599590; 25684123; 25689249; 25693118; 25704009; 25712931; 25738962; 25774715; 25774716; 25908663; 25980012; 26100631; 26158519; 26173909; 26203636; 26216893; 26232428; 26253422; 26567013; 26572062; 26572063; 26682985; 26686473; 26814970; 27103670; 27156449; 27292635; 27339979; 27516385; 27626380; 27693356; 27709293; 27760760; 27808091; 27911804; 27914912; 27917412; 27939674; 28345580; 28404595; 28446458; 28614717; 28636595; 28760936; 28771586; 28939441; 28951422; 28990935; 28991049; 29030458; 29038248; 29045901; 29061850; 29146733; 29176737; 29262324; 29281837; 29339744; 29353059; 29358279; 29414788; 29472103; 29520027; 29539421; 29576451; 29588315; 29643381; 29728534; 29735414; 29774028; 29866797; 29873075; 29937272; 29972777; 29996103; 30021146; 30133699; 30135078; 30165781; 30170814; 30250284; 30266768; 30314759; 30381458; 30402707; 30451870; 30526845; 30538296; 30571969; 30587103; 30625325; 30718379; 30731209; 30748031; 30930743; 31036765; 31063608; 31064994; 31076358; 31131320; 31160363; 31173764; 31230050; 31405732; 31430539; 31440260; 31492850; 31586037; 31723262; 31836429; 31848486; 31923400; 31998283; 31999304; 32002713; 32041990; 32103022; 32111733; 32164878; 32234476; 32282854; 32298652; 32315377; 32332915; 32484462; 32555186; 32641037; 32758418; 32763970; 32855216; 32968210; 32989095; 33077977; 33097533; 33110056; 33124745; 33268895; 33278357; 33305736; 33398185; 33441602; 33721834; 33882312; 34349759; 34648590; 34676213; 34867993; 9491891; 9837723; |
| Motif | |
| Gene Encoded By | |
| Mass | 42,742 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda | 3.4.22.57;3.4.22.64; |