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]
1_MAEGN 6_ HRKKP 11_ LKVLE 16_ SLGKD 21_ FLTGV 26_ LDNLV 31_ EQNVL 36_ NWKEE 41_ EKKKY 46_ YDAKT 51_ EDKVR 56_ VMADS 61_ MQEKQ 66_ RMAGQ 71_ MLLQT 76_ FFNID 81_ QISPN 86_ KKAHP 91_ NMEAG 96_ PPESG 101_ ESTDA 106_ LKLCP 111_ HEEFL 116_ RLCKE 121_ RAEEI 126_ YPIKE 131_ RNNRT 136_ RLALI 141_ ICNTE 146_ FDHLP 151_ PRNGA 156_ DFDIT 161_ GMKEL 166_ LEGLD 171_ YSVDV 176_ EENLT 181_ ARDME 186_ SALRA 191_ FATRP 196_ EHKSS 201_ DSTFL 206_ VLMSH 211_ GILEG 216_ ICGTV 221_ HDEKK 226_ PDVLL 231_ YDTIF 236_ QIFNN 241_ RNCLS 246_ LKDKP 251_ KVIIV 256_ QACRG 261_ ANRGE 266_ LWVRD 271_ SPASL 276_ EVASS 281_ QSSEN 286_ LEEDA 291_ VYKTH 296_ VEKDF 301_ IAFCS 306_ STPHN 311_ VSWRD 316_ STMGS 321_ IFITQ 326_ LITCF 331_ QKYSW 336_ CCHLE 341_ EVFRK 346_ VQQSF 351_ ETPRA 356_ KAQMP 361_ TIERL 366_ SMTRY 371_FYLFP
1: Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:25119034, PubMed:26375003, PubMed:32109412, PubMed:34671164, PubMed:37001519, PubMed:37993712, PubMed:37993714). Also indirectly activates the NLRP3 and NLRP6 inflammasomes (PubMed:23516580, PubMed:26375003, PubMed:32109412, PubMed:7797510). Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18 (PubMed:15326478, PubMed:23516580, PubMed:26375003, PubMed:28314590, PubMed:32109412, PubMed:37993712, PubMed:37993714, PubMed:7797510). Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B (PubMed:25119034, PubMed:25121752, PubMed:26375003, PubMed:31268602, PubMed:32109412, PubMed:37993712, PubMed:37993714). In the non-canonical inflammasome, CASP4 is activated by direct binding to the lipid A moiety of LPS without the need of an upstream sensor (PubMed:25119034, PubMed:25121752, PubMed:29520027, PubMed:32510692, PubMed:32581219, PubMed:37993712). LPS-binding promotes CASP4 activation and CASP4-mediated cleavage of GSDMD and IL18, followed by IL18 secretion through the GSDMD pore, pyroptosis of infected cells and their extrusion into the gut lumen (PubMed:25119034, PubMed:25121752, PubMed:37993712, PubMed:37993714). Also indirectly promotes secretion of mature cytokines (IL1A and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes (PubMed:26375003, PubMed:32109412). Involved in NLRP3-dependent CASP1 activation and IL1B secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin (PubMed:22246630, PubMed:23516580, PubMed:24879791, PubMed:25964352, PubMed:26173988, PubMed:26174085, PubMed:26508369). 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 secretion (PubMed:33377178). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (PubMed:26508369). The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria (By similarity). Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection (PubMed:25121752, PubMed:25964352). Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown (By similarity). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752, PubMed:25964352, PubMed:26375003). May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC) (By similarity). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains (PubMed:15123740, PubMed:22246630, PubMed:23661706). 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). Catalyzes cleavage and maturation of IL18; IL18 processing also depends of the exosite interface on CASP4 (PubMed:15326478, PubMed:37993712, PubMed:37993714). In contrast, it does not directly process IL1B (PubMed:7743998, PubMed:7797510, PubMed:7797592). During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation (PubMed:28314590)
2: (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