CASP6_MOUSE
ID CASP6_MOUSE Reviewed; 276 AA.
AC O08738;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-JUL-1997, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=Caspase-6 {ECO:0000303|PubMed:9038361};
DE Short=CASP-6 {ECO:0000303|PubMed:9038361};
DE EC=3.4.22.59 {ECO:0000269|PubMed:22555455, ECO:0000269|PubMed:25231987};
DE AltName: Full=Apoptotic protease Mch-2 {ECO:0000303|PubMed:9038361};
DE Contains:
DE RecName: Full=Caspase-6 subunit p18 {ECO:0000250|UniProtKB:P55212};
DE Contains:
DE RecName: Full=Caspase-6 subunit p11 {ECO:0000250|UniProtKB:P55212};
DE Flags: Precursor;
GN Name=Casp6 {ECO:0000312|MGI:MGI:1312921};
GN Synonyms=Mch2 {ECO:0000303|PubMed:9038361};
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=C3H/An;
RX PubMed=9038361; DOI=10.1016/s0014-5793(97)00026-4;
RA van de Craen M., Vandenabeele P., Declercq W., van den Brande I.,
RA van Loo G., Molemans F., Schotte P., van Criekinge W., Beyaert R.,
RA Fiers W.;
RT "Characterization of seven murine caspase family members.";
RL FEBS Lett. 403:61-69(1997).
RN [2]
RP DISRUPTION PHENOTYPE.
RX PubMed=11062535; DOI=10.1038/81343;
RA Zheng T.S., Hunot S., Kuida K., Momoi T., Srinivasan A., Nicholson D.W.,
RA Lazebnik Y., Flavell R.A.;
RT "Deficiency in caspase-9 or caspase-3 induces compensatory caspase
RT activation.";
RL Nat. Med. 6:1241-1247(2000).
RN [3]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=18981099; DOI=10.4049/jimmunol.181.10.6810;
RA Watanabe C., Shu G.L., Zheng T.S., Flavell R.A., Clark E.A.;
RT "Caspase 6 regulates B cell activation and differentiation into plasma
RT cells.";
RL J. Immunol. 181:6810-6819(2008).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-62, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brown adipose tissue, Heart, Kidney, Liver, Lung, Spleen, and
RC Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22555455; DOI=10.1038/cdd.2012.55;
RA Robert G., Puissant A., Dufies M., Marchetti S., Jacquel A., Cluzeau T.,
RA Colosetti P., Belhacene N., Kahle P., Da Costa C.A., Luciano F.,
RA Checler F., Auberger P.;
RT "The caspase 6 derived N-terminal fragment of DJ-1 promotes apoptosis via
RT increased ROS production.";
RL Cell Death Differ. 19:1769-1778(2012).
RN [6]
RP FUNCTION, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=23695670; DOI=10.1038/ncomms2910;
RA Cusack C.L., Swahari V., Hampton Henley W., Michael Ramsey J., Deshmukh M.;
RT "Distinct pathways mediate axon degeneration during apoptosis and axon-
RT specific pruning.";
RL Nat. Commun. 4:1876-1876(2013).
RN [7]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=25231987; DOI=10.1074/jbc.m114.583419;
RA Suzuki J., Imanishi E., Nagata S.;
RT "Exposure of phosphatidylserine by Xk-related protein family members during
RT apoptosis.";
RL J. Biol. Chem. 289:30257-30267(2014).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29863787; DOI=10.1111/imcb.12172;
RA Watanabe C., Shu G.L., Giltiay N.V., Clark E.A.;
RT "Regulation of B-lineage cells by caspase 6.";
RL Immunol. Cell Biol. 96:1072-1082(2018).
RN [9]
RP FUNCTION, INTERACTION WITH RIPK3, ACTIVE SITE, AND MUTAGENESIS OF CYS-146.
RX PubMed=32298652; DOI=10.1016/j.cell.2020.03.040;
RA Zheng M., Karki R., Vogel P., Kanneganti T.D.;
RT "Caspase-6 is a key regulator of innate immunity, inflammasome activation,
RT and host defense.";
RL Cell 181:674-687(2020).
RN [10]
RP FUNCTION.
RX PubMed=32029622; DOI=10.1126/science.aay0542;
RA Zhao P., Sun X., Chaggan C., Liao Z., In Wong K., He F., Singh S.,
RA Loomba R., Karin M., Witztum J.L., Saltiel A.R.;
RT "An AMPK-caspase-6 axis controls liver damage in nonalcoholic
RT steatohepatitis.";
RL Science 367:652-660(2020).
CC -!- FUNCTION: Cysteine protease that plays essential roles in programmed
CC cell death, axonal degeneration, development and innate immunity
CC (PubMed:18981099, PubMed:22555455, PubMed:23695670, PubMed:32298652).
CC Acts as a non-canonical executioner caspase during apoptosis: localizes
CC in the nucleus and cleaves the nuclear structural protein NUMA1 and
CC lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation (By
CC similarity). Lamin-A/LMNA cleavage is required for chromatin
CC condensation and nuclear disassembly during apoptotic execution (By
CC similarity). Acts as a regulator of liver damage by promoting
CC hepatocyte apoptosis: in absence of phosphorylation by AMP-activated
CC protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome
CC c release, thereby participating in nonalcoholic steatohepatitis
CC (PubMed:32029622). Cleaves PARK7/DJ-1 in cells undergoing apoptosis
CC (PubMed:22555455). Involved in intrinsic apoptosis by mediating
CC cleavage of RIPK1 (By similarity). Furthermore, cleaves many
CC transcription factors such as NF-kappa-B and cAMP response element-
CC binding protein/CREBBP (By similarity). Cleaves phospholipid scramblase
CC proteins XKR4 and XKR9 (PubMed:25231987). In addition to apoptosis,
CC involved in different forms of programmed cell death (PubMed:32298652).
CC Plays an essential role in defense against viruses by acting as a
CC central mediator of the ZBP1-mediated pyroptosis, apoptosis, and
CC necroptosis (PANoptosis), independently of its cysteine protease
CC activity (PubMed:32298652). PANoptosis is a unique inflammatory
CC programmed cell death, which provides a molecular scaffold that allows
CC the interactions and activation of machinery required for
CC inflammasome/pyroptosis, apoptosis and necroptosis (PubMed:32298652).
CC Mechanistically, interacts with RIPK3 and enhances the interaction
CC between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome
CC activation and cell death (PubMed:32298652). Plays an essential role in
CC axon degeneration during axon pruning which is the remodeling of axons
CC during neurogenesis but not apoptosis (PubMed:23695670). Regulates B-
CC cell programs both during early development and after antigen
CC stimulation (PubMed:18981099, PubMed:29863787).
CC {ECO:0000250|UniProtKB:P55212, ECO:0000269|PubMed:18981099,
CC ECO:0000269|PubMed:22555455, ECO:0000269|PubMed:23695670,
CC ECO:0000269|PubMed:25231987, ECO:0000269|PubMed:29863787,
CC ECO:0000269|PubMed:32029622, ECO:0000269|PubMed:32298652}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Strict requirement for Asp at position P1 and has a preferred
CC cleavage sequence of Val-Glu-His-Asp-|-.; EC=3.4.22.59;
CC Evidence={ECO:0000269|PubMed:22555455, ECO:0000269|PubMed:25231987};
CC -!- ACTIVITY REGULATION: During activation, the N-terminal disordered
CC prodomain is removed by cleavage. Concomitantly, double cleavage gives
CC rise to a large 18-kDa and a small 11-kDa subunit. The two large and
CC two small subunits then assemble to form the active CASP6 complex. Can
CC be cleaved and activated by different caspases, depending on the
CC context. Cleaved and activated by caspase-8 (CASP8) and subsequently by
CC caspase-3 (CASP3). Can also undergo autoactivation by mediating
CC autocleavage at Asp-162 and Asp-175, while it is not able to cleave its
CC N-terminal disordered prodomain. Intramolecular cleavage at Asp-175 is
CC a prerequisite for CASP6 self-activation. Cleaved and activated by
CC CASP1 in neurons, possibly in the context of inflammation.
CC Phosphorylation at Ser-239 inhibits autocleavage, preventing caspase
CC activation. {ECO:0000250|UniProtKB:P55212}.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel arranged
CC heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11)
CC subunit. Interacts with BIRC6/bruce. Interacts with RIPK3.
CC {ECO:0000250|UniProtKB:P55212}.
CC -!- SUBUNIT: [Caspase-6 subunit p18]: Heterotetramer that consists of two
CC anti-parallel arranged heterodimers, each one formed by a 18 kDa
CC (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.
CC {ECO:0000250|UniProtKB:P55212}.
CC -!- SUBUNIT: [Caspase-6 subunit p11]: Heterotetramer that consists of two
CC anti-parallel arranged heterodimers, each one formed by a 18 kDa
CC (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.
CC {ECO:0000250|UniProtKB:P55212}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P55212}. Nucleus
CC {ECO:0000250|UniProtKB:P55212}.
CC -!- TISSUE SPECIFICITY: Highly expressed in lung, liver, kidney, testis,
CC and heart. Lower levels in spleen, skeletal muscle and brain. Expressed
CC in neurons. {ECO:0000269|PubMed:23695670}.
CC -!- DOMAIN: The N-terminal disordered prodomain is required to prevent
CC self-activation. {ECO:0000250|UniProtKB:P55212}.
CC -!- DOMAIN: The Tri-arginine exosite is required to recruit substrates for
CC hydrolysis. {ECO:0000250|UniProtKB:P55212}.
CC -!- DOMAIN: Undergoes helix-strand structural transitions upon substrate-
CC binding: the 130's region interconverts between an inactive helical
CC state and the canonically active strand state. Other caspases rest
CC constitutively in the strand conformation before and after substrate-
CC binding. {ECO:0000250|UniProtKB:P55212}.
CC -!- PTM: Phosphorylated by NUAK1; phosphorylation inhibits self-activation.
CC Phosphorylation at Ser-239 by AMP-activated protein kinase (PRKAA1 or
CC PRKAA2) inhibits autocleavage, preventing caspase activation, thereby
CC preventing hepatocyte apoptosis. {ECO:0000250|UniProtKB:P55212}.
CC -!- PTM: Palmitoylation by ZDHHC17 blocks dimerization and subsequent
CC activation, leading to inhibit the cysteine protease activity.
CC {ECO:0000250|UniProtKB:P55212}.
CC -!- PTM: Can be cleaved and activated by different caspases, depending on
CC the context. Cleaved and activated by caspase-8 (CASP8) and
CC subsequently by caspase-3 (CASP3). Can also undergo autoactivation by
CC mediating autocleavage at Asp-162 and Asp-175, while it is not able to
CC cleave its N-terminal disordered prodomain. Cleaved and activated by
CC CASP1, possibly in the context of inflammation.
CC {ECO:0000250|UniProtKB:P55212}.
CC -!- DISRUPTION PHENOTYPE: Casp6-knockout mice are grossly normal, breed
CC with Mendelian ratio, and are only slightly protected from anti-
CC Fas/CD95-induced cell death (PubMed:11062535). Casp6-deficient neurons
CC undergo apoptosis and exhibit soma and axon degeneration just as wild
CC type neurons (PubMed:23695670). While Casp6-deficiency is able to block
CC axon degeneration with local deprivation, it is incapable of doing so
CC with global deprivation (PubMed:23695670). In addition, B-cell
CC differentiation into plasma cells is accelerated in deletion mutants
CC compared to wild-type (PubMed:18981099, PubMed:29863787). Casp6-
CC knockout mice are more susceptible to influenza virus infection
CC (PubMed:32298652). {ECO:0000269|PubMed:11062535,
CC ECO:0000269|PubMed:18981099, ECO:0000269|PubMed:23695670,
CC ECO:0000269|PubMed:29863787, ECO:0000269|PubMed:32298652}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR EMBL; Y13087; CAA73529.1; -; mRNA.
DR CCDS; CCDS17838.1; -.
DR RefSeq; NP_033941.3; NM_009811.4.
DR AlphaFoldDB; O08738; -.
DR SMR; O08738; -.
DR BioGRID; 198498; 13.
DR ComplexPortal; CPX-3944; Caspase-6 complex.
DR STRING; 10090.ENSMUSP00000029626; -.
DR MEROPS; C14.005; -.
DR iPTMnet; O08738; -.
DR PhosphoSitePlus; O08738; -.
DR SwissPalm; O08738; -.
DR EPD; O08738; -.
DR jPOST; O08738; -.
DR PaxDb; O08738; -.
DR PeptideAtlas; O08738; -.
DR PRIDE; O08738; -.
DR ProteomicsDB; 265440; -.
DR Antibodypedia; 1733; 1154 antibodies from 43 providers.
DR DNASU; 12368; -.
DR Ensembl; ENSMUST00000029626; ENSMUSP00000029626; ENSMUSG00000027997.
DR GeneID; 12368; -.
DR KEGG; mmu:12368; -.
DR UCSC; uc008riq.3; mouse.
DR CTD; 839; -.
DR MGI; MGI:1312921; Casp6.
DR VEuPathDB; HostDB:ENSMUSG00000027997; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00940000155140; -.
DR HOGENOM; CLU_036904_2_0_1; -.
DR InParanoid; O08738; -.
DR OMA; PAEEYRM; -.
DR OrthoDB; 984395at2759; -.
DR PhylomeDB; O08738; -.
DR TreeFam; TF102023; -.
DR BRENDA; 3.4.22.59; 3474.
DR Reactome; R-MMU-111465; Apoptotic cleavage of cellular proteins.
DR Reactome; R-MMU-264870; Caspase-mediated cleavage of cytoskeletal proteins.
DR Reactome; R-MMU-352238; Breakdown of the nuclear lamina.
DR BioGRID-ORCS; 12368; 0 hits in 59 CRISPR screens.
DR ChiTaRS; Casp6; mouse.
DR PRO; PR:O08738; -.
DR Proteomes; UP000000589; Chromosome 3.
DR RNAct; O08738; protein.
DR Bgee; ENSMUSG00000027997; Expressed in small intestine Peyer's patch and 241 other tissues.
DR ExpressionAtlas; O08738; baseline and differential.
DR Genevisible; O08738; MM.
DR GO; GO:0030424; C:axon; ISO:MGI.
DR GO; GO:0008303; C:caspase complex; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0005739; C:mitochondrion; IEA:GOC.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0005730; C:nucleolus; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; ISS:UniProtKB.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB.
DR GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; ISO:MGI.
DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; ISO:MGI.
DR GO; GO:0002218; P:activation of innate immune response; ISS:UniProtKB.
DR GO; GO:0002525; P:acute inflammatory response to non-antigenic stimulus; ISO:MGI.
DR GO; GO:0006915; P:apoptotic process; IBA:GO_Central.
DR GO; GO:0007413; P:axonal fasciculation; ISO:MGI.
DR GO; GO:0072734; P:cellular response to staurosporine; ISO:MGI.
DR GO; GO:0030855; P:epithelial cell differentiation; IEA:Ensembl.
DR GO; GO:0097284; P:hepatocyte apoptotic process; ISS:UniProtKB.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0060545; P:positive regulation of necroptotic process; ISS:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:0046670; P:positive regulation of retinal cell programmed cell death; ISO:MGI.
DR GO; GO:0016540; P:protein autoprocessing; ISS:UniProtKB.
DR GO; GO:0006508; P:proteolysis; ISO:MGI.
DR GO; GO:0070269; P:pyroptosis; ISS:UniProtKB.
DR GO; GO:1901028; P:regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway; IC:ComplexPortal.
DR GO; GO:0034097; P:response to cytokine; ISO:MGI.
DR GO; GO:0009749; P:response to glucose; ISO:MGI.
DR GO; GO:0042542; P:response to hydrogen peroxide; ISO:MGI.
DR GO; GO:0010039; P:response to iron ion; ISO:MGI.
DR CDD; cd00032; CASc; 1.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR037554; Caspase_6.
DR InterPro; IPR033139; Caspase_cys_AS.
DR InterPro; IPR016129; Caspase_his_AS.
DR InterPro; IPR002398; Pept_C14.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR PANTHER; PTHR10454:SF206; PTHR10454:SF206; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00115; CASc; 1.
DR SUPFAM; SSF52129; SSF52129; 1.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS01121; CASPASE_HIS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Autocatalytic cleavage; Cytoplasm; Hydrolase; Lipoprotein;
KW Nucleus; Palmitate; Phosphoprotein; Protease; Reference proteome;
KW Thiol protease; Zymogen.
FT PROPEP 1..5
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT /id="PRO_0000004612"
FT CHAIN 6..162
FT /note="Caspase-6 subunit p18"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT /id="PRO_0000004613"
FT PROPEP 163..175
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT /id="PRO_0000004614"
FT CHAIN 176..276
FT /note="Caspase-6 subunit p11"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT /id="PRO_0000004615"
FT REGION 25..27
FT /note="Tri-arginine exosite"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT REGION 108..125
FT /note="130's region"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT ACT_SITE 104
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT ACT_SITE 146
FT /evidence="ECO:0000305|PubMed:32298652"
FT MOD_RES 62
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT MOD_RES 239
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT LIPID 246
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT LIPID 259
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:P55212"
FT MUTAGEN 146
FT /note="C->A: Does not affect ability to promote ZBP1-
FT mediated pyroptosis, apoptosis, and necroptosis
FT (PANoptosis)."
FT /evidence="ECO:0000269|PubMed:32298652"
SQ SEQUENCE 276 AA; 31595 MW; 5965DE9321126B6C CRC64;
MTETDGFYKS REVFDPAEQY KMDHKRRGVA LIFNHERFFW HLTLPERRGT NADRDNLTRR
FSDLGFEVKC FNDLRAEELL LKIHEVSTSS HIDADCFICV FLSHGEGNHV YAYDAKIEIQ
TLTGLFKGDK CQSLVGKPKI FIIQACRGSQ HDVPVVPLDM VDHQTDKLDN VTQVDAASVY
TLPAGADFLM CYSVAEGYYS HRETVNGSWY IQDLCEMLAR YGSSLEFTEL LTLVNRKVSQ
RRVDFCKDPD AIGKKQVPCF ASMLTKKLHF CPKPSK
