CASP4
entrez
837
canonical
uniprot
P49662
canonical
ensembl
ENSG00000196954
resolver
ensp
ENSP00000376857
resolver
ensp
ENSP00000388566
resolver
genesymbol
CASP4
resolver
genesymbol_syn
ICH2
resolver
hgnc
HGNC:1505
resolver
uniprot
A2NHL8
resolver
uniprot
A2NHL9
resolver
uniprot
A2NHM0
resolver
uniprot
B3KPZ9
resolver
uniprot
B4DJH5
resolver
uniprot
B4E2D2
resolver
uniprot
O95601
resolver
uniprot
Q7KYX7
resolver
uniprot
Q9UG96
resolver
uniprot_entry
CASP4_HUMAN
resolver
uniprot_sec
A2NHL8
resolver
uniprot_sec
A2NHL9
resolver
uniprot_sec
A2NHM0
resolver
uniprot_sec
B3KPZ9
resolver
uniprot_sec
B4DJH5
resolver
uniprot_sec
B4E2D2
resolver
uniprot_sec
O95601
resolver
uniprot_sec
Q7KYX7
resolver
uniprot_sec
Q9UG96
resolver
activity_regulation
ACTIVITY REGULATION: Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner (PubMed:25119034, PubMed:29520027). In addition to LPS, CASP4/CASP11 may also be activated by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC), in dendritic cells, promoting adaptive immunity (By similarity). The role of oxPAPC is however unclear and another report suggests that oxPAPC competes with LPS-binding and inhibits the non-canonical inflammasome in macrophages (PubMed:29520027). {ECO:0000250|UniProtKB:P70343, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:29520027}.
uniprot
proteins
amino_acid_sequence
MAEGNHRKKPLKVLESLGKDFLTGVLDNLVEQNVLNWKEEEKKKYYDAKTEDKVRVMADSMQEKQRMAGQMLLQTFFNIDQISPNKKAHPNMEAGPPESGESTDALKLCPHEEFLRLCKERAEEIYPIKERNNRTRLALIICNTEFDHLPPRNGADFDITGMKELLEGLDYSVDVEENLTARDMESALRAFATRPEHKSSDSTFLVLMSHGILEGICGTVHDEKKPDVLLYDTIFQIFNNRNCLSLKDKPKVIIVQACRGANRGELWVRDSPASLEVASSQSSENLEEDAVYKTHVEKDFIAFCSSTPHNVSWRDSTMGSIFITQLITCFQKYSWCCHLEEVFRKVQQSFETPRAKAQMPTIERLSMTRYFYLFPGN
uniprot
proteins
ec_number
3.4.22.57
uniprot
proteins
function
FUNCTION: 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). {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:29520027, ECO:0000269|PubMed:31268602, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32510692, ECO:0000269|PubMed:32581219, ECO:0000269|PubMed:33377178, ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:37001519, ECO:0000269|PubMed:37993714, 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}.
uniprot
proteins
mass_dalton
43262
uniprot
proteins
mutagenesis
MUTAGEN 152; /note="R->A: Abolished ability to cleave IL18."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 212; /note="I->D: Abolished ability to cleave IL18; when associated with D-261."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 258; /note="C->A: Loss of enzymatic activity. Loss of LPS-induced pyroptosis. No effect on the interaction with LPS. Decrease in cell death induced by TMEM214 overexpression. Does not support IL1B and IL18 secretion following UVB irradiation."; /evidence="ECO:0000269|PubMed:22246630, ECO:0000269|PubMed:23661706, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714"; MUTAGEN 258; /note="C->S: Loss of autocatalysis."; /evidence="ECO:0000269|PubMed:7743998"; MUTAGEN 261; /note="A->D: Abolished ability to cleave IL18; when associated with D-212."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 267; /note="W->L,N: Abolished interaction with Gasdermin-D (GSDMD) and ability to mediate its cleavage. Abolished binding to IL18 and ability to mediate its cleavage."; /evidence="ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714"; MUTAGEN 269; /note="R->D: Abolished binding to IL18 and ability to mediate its cleavage."; /evidence="ECO:0000269|PubMed:37993712"; MUTAGEN 270; /note="D->A: Abolished autoprocessing and ability to form a heterotetramer composed of Caspase-4 subunit p10 and Caspase-4 subunit p20, preventing ability to cleave GSDMD and induce pyroptosis."; /evidence="ECO:0000269|PubMed:32109412"; MUTAGEN 289; /note="D->A: Abolished autoprocessing."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 291; /note="V->N: Abolished interaction with Gasdermin-D (GSDMD) and ability to mediate its cleavage. Strongly decreased ability to cleave IL18."; /evidence="ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:37993714"; MUTAGEN 293; /note="K->A: Strongly decreased ability to cleave IL18."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 314; /note="R->A: Abolished ability to cleave Gasdermin-D (GSDMD). Abolished ability to cleave IL18."; /evidence="ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:37993714"; MUTAGEN 321; /note="I->D: Abolished ability to cleave IL18."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 356; /note="K->D: Abolished binding to IL18 and ability to mediate its cleavage."; /evidence="ECO:0000269|PubMed:37993712
uniprot
proteins
post_translational_modification
PTM: In response to activation signals, undergoes autoproteolytic cleavage and activation. {ECO:0000269|PubMed:15123740, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:37993714, 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, ECO:0000269|PubMed:35338844, ECO:0000269|PubMed:36624349, ECO:0000269|PubMed:37014865}.
uniprot
proteins
protein_family
Peptidase C14A family
uniprot
proteins
pubmed
10986288
uniprot
proteins
pubmed
11230166
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15123740
uniprot
proteins
pubmed
15326478
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16554811
uniprot
proteins
pubmed
16893518
uniprot
proteins
pubmed
18511561
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
22246630
uniprot
proteins
pubmed
22814378
uniprot
proteins
pubmed
23516580
uniprot
proteins
pubmed
23661706
uniprot
proteins
pubmed
24879791
uniprot
proteins
pubmed
25119034
uniprot
proteins
pubmed
25121752
uniprot
proteins
pubmed
25695505
uniprot
proteins
pubmed
25964352
uniprot
proteins
pubmed
26173988
uniprot
proteins
pubmed
26174085
uniprot
proteins
pubmed
26375003
uniprot
proteins
pubmed
26508369
uniprot
proteins
pubmed
28314590
uniprot
proteins
pubmed
29077095
uniprot
proteins
pubmed
29520027
uniprot
proteins
pubmed
30692621
uniprot
proteins
pubmed
31268602
uniprot
proteins
pubmed
32109412
uniprot
proteins
pubmed
32510692
uniprot
proteins
pubmed
32581219
uniprot
proteins
pubmed
33377178
uniprot
proteins
pubmed
34671164
uniprot
proteins
pubmed
35338844
uniprot
proteins
pubmed
36624349
uniprot
proteins
pubmed
37001519
uniprot
proteins
pubmed
37014865
uniprot
proteins
pubmed
37993712
uniprot
proteins
pubmed
37993714
uniprot
proteins
pubmed
7743998
uniprot
proteins
pubmed
7797510
uniprot
proteins
pubmed
7797592
uniprot
proteins
sequence_length
377
uniprot
proteins
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}.
uniprot
proteins