CASP6
entrez
839
canonical
uniprot
P55212
canonical
ensembl
ENSG00000138794
resolver
ensp
ENSP00000265164
resolver
ensp
ENSP00000285333
resolver
ensp
ENSP00000728845
resolver
genesymbol
CASP6
resolver
genesymbol_syn
MCH2
resolver
hgnc
HGNC:1507
resolver
uniprot
Q9BQE7
resolver
uniprot_entry
CASP6_HUMAN
resolver
uniprot_sec
Q9BQE7
resolver
activity_regulation
ACTIVITY REGULATION: During activation, the N-terminal disordered prodomain is removed by cleavage (PubMed:19133298, PubMed:28864531, PubMed:8663580, PubMed:8900201). Concomitantly, double cleavage gives rise to a large 18-kDa and a small 11-kDa subunit (PubMed:19133298, PubMed:8663580). The two large and two small subunits then assemble to form the active CASP6 complex (PubMed:8663580). Can be cleaved and activated by different caspases, depending on the context (PubMed:19133298, PubMed:9463409). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Intramolecular cleavage at Asp-193 is a prerequisite for CASP6 self-activation (PubMed:20890311, PubMed:28864531). Cleaved and activated by CASP1 in neurons, possibly in the context of inflammation (PubMed:16123779). Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase activation (PubMed:15273717, PubMed:22433863, PubMed:22483120, PubMed:32029622). Specifically inhibited by compound 3 (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone) (PubMed:23227217). {ECO:0000269|PubMed:15273717, ECO:0000269|PubMed:16123779, ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:22433863, ECO:0000269|PubMed:22483120, ECO:0000269|PubMed:23227217, ECO:0000269|PubMed:28864531, ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:8663580, ECO:0000269|PubMed:8900201, ECO:0000269|PubMed:9463409}.
uniprot
proteins
amino_acid_sequence
MSSASGLRRGHPAGGEENMTETDAFYKREMFDPAEKYKMDHRRRGIALIFNHERFFWHLTLPERRGTCADRDNLTRRFSDLGFEVKCFNDLKAEELLLKIHEVSTVSHADADCFVCVFLSHGEGNHIYAYDAKIEIQTLTGLFKGDKCHSLVGKPKIFIIQACRGNQHDVPVIPLDVVDNQTEKLDTNITEVDAASVYTLPAGADFLMCYSVAEGYYSHRETVNGSWYIQDLCEMLGKYGSSLEFTELLTLVNRKVSQRRVDFCKDPSAIGKKQVPCFASMLTKKLHFFPKSN
uniprot
proteins
ec_number
3.4.22.59
uniprot
proteins
function
FUNCTION: Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity (PubMed:19133298, PubMed:22858542, PubMed:27032039, PubMed:28864531, PubMed:30420425, PubMed:32298652, PubMed:8663580). Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation (PubMed:11953316, PubMed:17401638, PubMed:8663580, PubMed:9463409). Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution (PubMed:11953316). Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis (PubMed:32029622). Cleaves PARK7/DJ-1 in cells undergoing apoptosis (By similarity). Involved in intrinsic apoptosis by mediating cleavage of RIPK1 (PubMed:22858542). Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP (PubMed:10559921, PubMed:14657026). Cleaves phospholipid scramblase proteins XKR4 and XKR9 (By similarity). In addition to apoptosis, involved in different forms of programmed cell death (PubMed:32298652). Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity (PubMed:32298652). PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis (PubMed:32298652). Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death (PubMed:32298652). Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis (By similarity). Regulates B-cell programs both during early development and after antigen stimulation (By similarity). {ECO:0000250|UniProtKB:O08738, ECO:0000269|PubMed:10559921, ECO:0000269|PubMed:11953316, ECO:0000269|PubMed:14657026, ECO:0000269|PubMed:17401638, ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:22858542, ECO:0000269|PubMed:27032039, ECO:0000269|PubMed:28864531, ECO:0000269|PubMed:30420425, ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:32298652, ECO:0000269|PubMed:8663580, ECO:0000269|PubMed:9463409}.; FUNCTION: (Microbial infection) Proteolytically cleaves the N protein of coronaviruses such as MERS-CoV and SARS-CoV (PubMed:18155731, PubMed:35922005). The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes (PubMed:35922005). The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication (PubMed:35922005). {ECO:0000269|PubMed:18155731, ECO:0000269|PubMed:35922005}.
uniprot
proteins
mass_dalton
33310
uniprot
proteins
mutagenesis
MUTAGEN 23; /note="D->A: Abolished activation due to the presence of the N-terminal disordered prodomain. Abolished processing and subsequent activation; when associated with A-179 and A-193."; /evidence="ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:28864531"; MUTAGEN 42..44; /note="RRR->AAA: Decreased ability to hydrolyze substrates."; /evidence="ECO:0000269|PubMed:30420425"; MUTAGEN 121; /note="H->A: Catalytically inactive active-site mutant."; /evidence="ECO:0000269|PubMed:30420425"; MUTAGEN 135; /note="E->Q: Increased stability."; /evidence="ECO:0000269|PubMed:28154009"; MUTAGEN 163; /note="C->A,S: Catalytically inactive active-site mutant."; /evidence="ECO:0000269|PubMed:16123779, ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:19694615, ECO:0000269|PubMed:20890311, ECO:0000269|PubMed:28864531, ECO:0000269|PubMed:30420425"; MUTAGEN 179; /note="D->A: Abolished processing and subsequent activation; when associated with A-23 and A-193."; /evidence="ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:28864531"; MUTAGEN 193; /note="D->A: Abolished processing and subsequent activation; when associated with A-23 and A-179."; /evidence="ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:28864531"; MUTAGEN 257; /note="S->A: Abolished phosphorylation, leading to caspase-6 activation."; /evidence="ECO:0000269|PubMed:15273717, ECO:0000269|PubMed:32029622"; MUTAGEN 257; /note="S->D: Phospho-mimetic mutant; prevents caspase-6 autoactivation."; /evidence="ECO:0000269|PubMed:22483120, ECO:0000269|PubMed:32029622"; MUTAGEN 257; /note="S->E: Phospho-mimetic mutant; loss of self-activation."; /evidence="ECO:0000269|PubMed:22433863, ECO:0000269|PubMed:32029622"; MUTAGEN 264; /note="C->S: Reduced palmitoylation, leading to increased cysteine protease activity."; /evidence="ECO:0000269|PubMed:27911442"; MUTAGEN 277; /note="C->S: Reduced palmitoylation, leading to increased cysteine protease activity."; /evidence="ECO:0000269|PubMed:27911442
uniprot
proteins
post_translational_modification
PTM: Phosphorylated by NUAK1; phosphorylation inhibits self-activation (PubMed:15273717, PubMed:22483120). Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage, preventing caspase activation, thereby preventing hepatocyte apoptosis (PubMed:32029622). {ECO:0000269|PubMed:15273717, ECO:0000269|PubMed:22483120, ECO:0000269|PubMed:32029622}.; PTM: Palmitoylation by ZDHHC17 blocks dimerization and subsequent activation, leading to inhibit the cysteine protease activity. {ECO:0000269|PubMed:27911442}.; PTM: Can be cleaved and activated by different caspases, depending on the context (PubMed:19133298, PubMed:28864531). Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3) (PubMed:9463409). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain (PubMed:19133298, PubMed:28864531). Cleaved and activated by CASP1, possibly in the context of inflammation (PubMed:16123779). {ECO:0000269|PubMed:16123779, ECO:0000269|PubMed:19133298, ECO:0000269|PubMed:28864531, ECO:0000269|PubMed:9463409}.
uniprot
proteins
protein_family
Peptidase C14A family
uniprot
proteins
pubmed
10559921
uniprot
proteins
pubmed
11953316
uniprot
proteins
pubmed
14657026
uniprot
proteins
pubmed
15200957
uniprot
proteins
pubmed
15273717
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
16123779
uniprot
proteins
pubmed
17401638
uniprot
proteins
pubmed
18155731
uniprot
proteins
pubmed
19133298
uniprot
proteins
pubmed
19694615
uniprot
proteins
pubmed
20890311
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22433863
uniprot
proteins
pubmed
22483120
uniprot
proteins
pubmed
22858542
uniprot
proteins
pubmed
23227217
uniprot
proteins
pubmed
27032039
uniprot
proteins
pubmed
27911442
uniprot
proteins
pubmed
28154009
uniprot
proteins
pubmed
28864531
uniprot
proteins
pubmed
30420425
uniprot
proteins
pubmed
32029622
uniprot
proteins
pubmed
32298652
uniprot
proteins
pubmed
35922005
uniprot
proteins
pubmed
7796396
uniprot
proteins
pubmed
8663580
uniprot
proteins
pubmed
8900201
uniprot
proteins
pubmed
9463409
uniprot
proteins
sequence_length
293
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27911442}. Nucleus {ECO:0000269|PubMed:27911442}.
uniprot
proteins