Casp4
entrez
12363
canonical
uniprot
P70343
canonical
ensembl
ENSMUSG00000033538
resolver
ensp
ENSMUSP00000027012
resolver
genesymbol
Casp4
resolver
genesymbol_syn
Casp11
resolver
genesymbol_syn
Caspl
resolver
genesymbol_syn
Ich3
resolver
uniprot
C6L648
resolver
uniprot
O08735
resolver
uniprot
Q3TAF3
resolver
uniprot
Q6P8H1
resolver
uniprot_entry
CASP4_MOUSE
resolver
uniprot_sec
C6L648
resolver
uniprot_sec
O08735
resolver
uniprot_sec
Q3TAF3
resolver
uniprot_sec
Q6P8H1
resolver
activity_regulation
ACTIVITY REGULATION: Activated by homooligomerization induced by direct binding to cytosolic LPS, in a TLR4-independent manner (PubMed:22002608, PubMed:23348507, PubMed:23887873, PubMed:24031018, PubMed:25119034). 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 (PubMed:27103670). 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:0000269|PubMed:22002608, ECO:0000269|PubMed:23348507, ECO:0000269|PubMed:23887873, ECO:0000269|PubMed:24031018, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:27103670, ECO:0000269|PubMed:29520027}.
uniprot
proteins
amino_acid_sequence
MAENKHPDKPLKVLEQLGKEVLTEYLEKLVQSNVLKLKEEDKQKFNNAERSDKRWVFVDAMKKKHSKVGEMLLQTFFSVDPGSHHGEANLEMEEPEESLNTLKLCSPEEFTRLCREKTQEIYPIKEANGRTRKALIICNTEFKHLSLRYGANFDIIGMKGLLEDLGYDVVVKEELTAEGMESEMKDFAALSEHQTSDSTFLVLMSHGTLHGICGTMHSEKTPDVLQYDTIYQIFNNCHCPGLRDKPKVIIVQACRGGNSGEMWIRESSKPQLCRGVDLPRNMEADAVKLSHVEKDFIAFYSTTPHHLSYRDKTGGSYFITRLISCFRKHACSCHLFDIFLKVQQSFEKASIHSQMPTIDRATLTRYFYLFPGN
uniprot
proteins
ec_number
3.4.22.64
uniprot
proteins
function
FUNCTION: Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis (PubMed:22002608, PubMed:23348507, PubMed:23887873, PubMed:24031018, PubMed:25119034, PubMed:30135078, PubMed:37001519, PubMed:38632402). Also indirectly activates the NLRP3 and NLRP6 inflammasomes (PubMed:26320999, PubMed:30392956, PubMed:37001519). Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS and GSDMD (PubMed:26375003, PubMed:28314590, PubMed:30392956, PubMed:38632402). In contrast to its human ortholog, does not cleave IL18 (PubMed:37993712, PubMed:37993714). 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 and IL18 (PubMed:22002608, PubMed:22895188, PubMed:23348507, PubMed:23887873, PubMed:24031018, PubMed:26320999, PubMed:26375003, PubMed:30135078, PubMed:30589883). In the non-canonical inflammasome, CASP4/CASP11 is activated by direct binding to the lipid A moiety of LPS without the need of an upstream sensor (PubMed:22002608, PubMed:23348507, PubMed:25119034, PubMed:37001519, PubMed:38632402). LPS-binding promotes CASP4/CASP11 activation and CASP4/CASP11-mediated cleavage of GSDMD, followed by pyroptosis of infected cells and their extrusion into the gut lumen (PubMed:22002608, PubMed:23348507, PubMed:25119034, PubMed:38632402). Also indirectly promotes secretion of mature cytokines (IL1A, IL18 and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes (By similarity). Involved in NLRP3-dependent CASP1 activation and IL1B and IL18 secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin (PubMed:26320999). 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). Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity (By similarity). The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria (PubMed:23348507). Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection (PubMed:25121752, PubMed:26375003, PubMed:34671164). Activation of the non-canonical inflammasome in brain endothelial cells can lead to excessive pyroptosis, leading to blood-brain barrier breakdown (PubMed:38632402). Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation (PubMed:25121752). 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) (PubMed:27103670). Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4/CASP11 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part (PubMed:32109412, PubMed:32554464). 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:22895188, ECO:0000269|PubMed:23348507, ECO:0000269|PubMed:23887873, ECO:0000269|PubMed:24031018, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:26320999, ECO:0000269|PubMed:26375003, ECO:0000269|PubMed:27103670, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:30135078, ECO:0000269|PubMed:30392956, ECO:0000269|PubMed:30589883, ECO:0000269|PubMed:32109412, ECO:0000269|PubMed:32554464, ECO:0000269|PubMed:34671164, ECO:0000269|PubMed:37001519, ECO:0000269|PubMed:37993712, ECO:0000269|PubMed:37993714, ECO:0000269|PubMed:38632402, ECO:0000269|PubMed:8702803, ECO:0000269|PubMed:9038361}.
uniprot
proteins
mass_dalton
42742
uniprot
proteins
mutagenesis
MUTAGEN 19; /note="K->E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 38; /note="K->E: No effect on LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with M-40."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 40; /note="E->M: No effect on LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-38."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 53; /note="K->E: Complete loss of LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-54 and A-55."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 54; /note="R->E: Complete loss of LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-53 and A-55."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 55; /note="W->A: Complete loss of LPS-binding, LPS-induced oligomerization, and LPS-induced pyroptosis; when associated with E-54 and A-55."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 62; /note="K->E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis; when associated with E-63 and E-64."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 63; /note="K->E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis; when associated with E-62 and E-64."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 64; /note="K->E: Severely attenuated LPS-binding, LPS-induced oligomerization and activation, and LPS-induced pyroptosis; when associated with E-62 and E-63."; /evidence="ECO:0000269|PubMed:25119034"; MUTAGEN 80; /note="D->N: Impaired NLRP6 inflammasome-dependent activation and release of IL1B and IL18."; /evidence="ECO:0000269|PubMed:30392956"; MUTAGEN 254; /note="C->A: Loss of catalytic activity and of autocatalytic processing. Loss of LPS-induced pyroptosis. No effect on the interaction with LPS."; /evidence="ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:25119034, ECO:0000269|PubMed:28314590, ECO:0000269|PubMed:30135078, ECO:0000269|PubMed:30392956"; MUTAGEN 254; /note="C->G: No cell death."; MUTAGEN 277; /note="D->N: Impaired NLRP6 inflammasome-dependent activation and release of IL1B and IL18."; /evidence="ECO:0000269|PubMed:30392956"; MUTAGEN 285; /note="D->A: Loss of autocatalytic processing and subsequent activation."; /evidence="ECO:0000269|PubMed:30135078"; MUTAGEN 285; /note="D->N: Impaired NLRP6 inflammasome-dependent activation and release of IL1B and IL18."; /evidence="ECO:0000269|PubMed:30392956"; MUTAGEN 289; /note="L->K: Does not promote ability to cleave IL18."; /evidence="ECO:0000269|PubMed:37993714"; MUTAGEN 310; /note="R->A: Abolished ability to cleave Gasdermin-D (GSDMD)."; /evidence="ECO:0000269|PubMed:34671164
uniprot
proteins
post_translational_modification
PTM: In response to activation signals, undergoes autoproteolytic cleavage and activation. {ECO:0000269|PubMed:22002608, ECO:0000269|PubMed:25121752, ECO:0000269|PubMed:30135078, 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}.
uniprot
proteins
protein_family
Peptidase C14A family
uniprot
proteins
pubmed
10986288
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16141072
uniprot
proteins
pubmed
16670335
uniprot
proteins
pubmed
19468303
uniprot
proteins
pubmed
22002608
uniprot
proteins
pubmed
22895188
uniprot
proteins
pubmed
23348507
uniprot
proteins
pubmed
23887873
uniprot
proteins
pubmed
24031018
uniprot
proteins
pubmed
25119034
uniprot
proteins
pubmed
25121752
uniprot
proteins
pubmed
26173909
uniprot
proteins
pubmed
26320999
uniprot
proteins
pubmed
26375003
uniprot
proteins
pubmed
26375259
uniprot
proteins
pubmed
27103670
uniprot
proteins
pubmed
28314590
uniprot
proteins
pubmed
29520027
uniprot
proteins
pubmed
30135078
uniprot
proteins
pubmed
30392956
uniprot
proteins
pubmed
30589883
uniprot
proteins
pubmed
30692621
uniprot
proteins
pubmed
32109412
uniprot
proteins
pubmed
32554464
uniprot
proteins
pubmed
34671164
uniprot
proteins
pubmed
37001519
uniprot
proteins
pubmed
37993712
uniprot
proteins
pubmed
37993714
uniprot
proteins
pubmed
38632402
uniprot
proteins
pubmed
8702803
uniprot
proteins
pubmed
9038361
uniprot
proteins
sequence_length
373
uniprot
proteins
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}.
uniprot
proteins