CFLAR_MOUSE
ID CFLAR_MOUSE Reviewed; 481 AA.
AC O35732; D3Z0W6; O35707; O35733;
DT 01-DEC-2000, integrated into UniProtKB/Swiss-Prot.
DT 25-OCT-2017, sequence version 3.
DT 03-AUG-2022, entry version 190.
DE RecName: Full=CASP8 and FADD-like apoptosis regulator;
DE AltName: Full=Caspase homolog;
DE Short=CASH;
DE AltName: Full=Caspase-eight-related protein;
DE Short=Casper;
DE AltName: Full=Caspase-like apoptosis regulatory protein;
DE Short=CLARP;
DE AltName: Full=Cellular FLICE-like inhibitory protein;
DE Short=c-FLIP;
DE AltName: Full=FADD-like antiapoptotic molecule 1;
DE Short=FLAME-1;
DE AltName: Full=Inhibitor of FLICE;
DE Short=I-FLICE;
DE AltName: Full=MACH-related inducer of toxicity;
DE Short=MRIT;
DE AltName: Full=Usurpin;
DE Contains:
DE RecName: Full=CASP8 and FADD-like apoptosis regulator subunit p43;
DE Contains:
DE RecName: Full=CASP8 and FADD-like apoptosis regulator subunit p12;
DE Flags: Precursor;
GN Name=Cflar; Synonyms=Cash;
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] (ISOFORMS 1 AND 2).
RC TISSUE=Liver, and Skin fibroblast;
RX PubMed=9289491; DOI=10.1074/jbc.272.32.19641;
RA Goltsev Y.V., Kovalenko A.V., Arnold E., Varfolomeev E.E.,
RA Brodianskii V.M., Wallach D.;
RT "CASH, a novel caspase homologue with death effector domains.";
RL J. Biol. Chem. 272:19641-19644(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Heart;
RX PubMed=9217161; DOI=10.1038/40657;
RA Irmler M., Thome M., Hahne M., Schneider P., Hofmann K., Steiner V.,
RA Bodmer J.-L., Schroeter M., Burns K., Mattmann C., Rimoldi D., French L.E.,
RA Tschopp J.;
RT "Inhibition of death receptor signals by cellular FLIP.";
RL Nature 388:190-195(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [4]
RP FUNCTION.
RX PubMed=10894163; DOI=10.1016/s1074-7613(00)80214-9;
RA Yeh W.-C., Itie A., Elia A.J., Ng M., Shu H.-B., Wakeham A., Mirtsos C.,
RA Suzuki N., Bonnard M., Goeddel D.V., Mak T.W.;
RT "Requirement for Casper (c-FLIP) in regulation of death receptor-induced
RT apoptosis and embryonic development.";
RL Immunity 12:633-642(2000).
RN [5]
RP FUNCTION.
RX PubMed=10602037;
RX DOI=10.1002/1521-4141(200001)30:1<155::aid-immu155>3.0.co;2-x;
RA Wang J., Lobito A.A., Shen F., Hornung F., Winoto A., Lenardo M.J.;
RT "Inhibition of Fas-mediated apoptosis by the B cell antigen receptor
RT through c-FLIP.";
RL Eur. J. Immunol. 30:155-163(2000).
RN [6]
RP INTERACTION WITH RIPK1.
RX PubMed=31519887; DOI=10.1038/s41467-019-12033-8;
RA Tang Y., Tu H., Zhang J., Zhao X., Wang Y., Qin J., Lin X.;
RT "K63-linked ubiquitination regulates RIPK1 kinase activity to prevent cell
RT death during embryogenesis and inflammation.";
RL Nat. Commun. 10:4157-4157(2019).
RN [7]
RP PROTEOLYTIC PROCESSING, MUTAGENESIS OF ASP-371 AND ASP-377, AND SITE.
RX PubMed=31511692; DOI=10.1016/j.immuni.2013.06.018;
RA Newton K., Wickliffe K.E., Dugger D.L., Maltzman A., Roose-Girma M.,
RA Dohse M., Komuves L., Webster J.D., Dixit V.M.;
RT "Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and
RT necroptosis.";
RL Nature 574:428-431(2019).
CC -!- FUNCTION: Apoptosis regulator protein which may function as a crucial
CC link between cell survival and cell death pathways in mammalian cells.
CC Acts as an inhibitor of TNFRSF6 mediated apoptosis. A proteolytic
CC fragment (p43) is likely retained in the death-inducing signaling
CC complex (DISC) thereby blocking further recruitment and processing of
CC caspase-8 at the complex. Full length and shorter isoforms have been
CC shown either to induce apoptosis or to reduce TNFRSF-triggered
CC apoptosis. Lacks enzymatic (caspase) activity (By similarity).
CC {ECO:0000250, ECO:0000269|PubMed:10602037,
CC ECO:0000269|PubMed:10894163}.
CC -!- SUBUNIT: TNFRSF6 stimulation triggers recruitment to the death-inducing
CC signaling complex (DISC) formed by TNFRSF6, FADD and CASP8 (By
CC similarity). A proteolytic fragment (p43) stays associated with the
CC DISC (By similarity). Interacts with RIPK1 (PubMed:31519887).
CC {ECO:0000250|UniProtKB:O15519, ECO:0000269|PubMed:31519887}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=FLIP-L, CASH alpha;
CC IsoId=O35732-1; Sequence=Displayed;
CC Name=2; Synonyms=FLIP-S, CASH beta;
CC IsoId=O35732-2; Sequence=VSP_000842, VSP_000843;
CC -!- TISSUE SPECIFICITY: Highly expressed in heart.
CC -!- DEVELOPMENTAL STAGE: At 9.5 and 10.5 dpc, highly expressed in
CC developing heart.
CC -!- INDUCTION: Isoform 1 but not isoform 2 is activated by BCR cross-
CC linking in primary B-cells.
CC -!- DOMAIN: The caspase domain lacks the active site residues involved in
CC catalysis.
CC -!- PTM: Proteolytically processed by CASP8 generating subunits p43 and
CC p12. {ECO:0000269|PubMed:31511692}.
CC -!- SIMILARITY: Belongs to the peptidase C14A family. {ECO:0000305}.
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DR EMBL; Y14041; CAA74368.1; -; mRNA.
DR EMBL; Y14042; CAA74369.1; -; mRNA.
DR EMBL; U97076; AAC53281.1; -; mRNA.
DR EMBL; AC112968; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS14978.1; -. [O35732-1]
DR CCDS; CCDS35582.1; -. [O35732-2]
DR RefSeq; NP_001276633.1; NM_001289704.2. [O35732-1]
DR RefSeq; NP_997536.1; NM_207653.5. [O35732-1]
DR RefSeq; XP_006495698.1; XM_006495635.3. [O35732-1]
DR RefSeq; XP_011236722.1; XM_011238420.2. [O35732-1]
DR RefSeq; XP_011236723.1; XM_011238421.2. [O35732-1]
DR RefSeq; XP_011236724.1; XM_011238422.1. [O35732-1]
DR RefSeq; XP_011236725.1; XM_011238423.2. [O35732-1]
DR RefSeq; XP_017169048.1; XM_017313559.1. [O35732-1]
DR AlphaFoldDB; O35732; -.
DR SMR; O35732; -.
DR BioGRID; 198686; 10.
DR IntAct; O35732; 2.
DR STRING; 10090.ENSMUSP00000109952; -.
DR MEROPS; C14.974; -.
DR iPTMnet; O35732; -.
DR PhosphoSitePlus; O35732; -.
DR PaxDb; O35732; -.
DR PRIDE; O35732; -.
DR ProteomicsDB; 281547; -. [O35732-1]
DR ProteomicsDB; 281548; -. [O35732-2]
DR Antibodypedia; 19934; 977 antibodies from 43 providers.
DR DNASU; 12633; -.
DR Ensembl; ENSMUST00000069333; ENSMUSP00000065107; ENSMUSG00000026031. [O35732-1]
DR Ensembl; ENSMUST00000114309; ENSMUSP00000109948; ENSMUSG00000026031. [O35732-2]
DR Ensembl; ENSMUST00000114313; ENSMUSP00000109952; ENSMUSG00000026031. [O35732-1]
DR GeneID; 12633; -.
DR KEGG; mmu:12633; -.
DR CTD; 8837; -.
DR MGI; MGI:1336166; Cflar.
DR VEuPathDB; HostDB:ENSMUSG00000026031; -.
DR eggNOG; KOG3573; Eukaryota.
DR GeneTree; ENSGT00530000064199; -.
DR InParanoid; O35732; -.
DR OMA; HIPEERY; -.
DR PhylomeDB; O35732; -.
DR Reactome; R-MMU-3371378; Regulation by c-FLIP.
DR Reactome; R-MMU-5218900; CASP8 activity is inhibited.
DR Reactome; R-MMU-5357905; Regulation of TNFR1 signaling.
DR Reactome; R-MMU-69416; Dimerization of procaspase-8.
DR Reactome; R-MMU-75158; TRAIL signaling.
DR BioGRID-ORCS; 12633; 34 hits in 71 CRISPR screens.
DR ChiTaRS; Cflar; mouse.
DR PRO; PR:O35732; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; O35732; protein.
DR Bgee; ENSMUSG00000026031; Expressed in granulocyte and 267 other tissues.
DR ExpressionAtlas; O35732; baseline and differential.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR GO; GO:0031264; C:death-inducing signaling complex; ISO:MGI.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0097342; C:ripoptosome; ISO:MGI.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0097199; F:cysteine-type endopeptidase activity involved in apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0097200; F:cysteine-type endopeptidase activity involved in execution phase of apoptosis; IBA:GO_Central.
DR GO; GO:0005123; F:death receptor binding; ISO:MGI.
DR GO; GO:0008047; F:enzyme activator activity; ISO:MGI.
DR GO; GO:0016504; F:peptidase activator activity; IDA:MGI.
DR GO; GO:0002020; F:protease binding; ISO:MGI.
DR GO; GO:0044877; F:protein-containing complex binding; ISO:MGI.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IBA:GO_Central.
DR GO; GO:0006915; P:apoptotic process; IMP:MGI.
DR GO; GO:0071732; P:cellular response to nitric oxide; ISO:MGI.
DR GO; GO:0070266; P:necroptotic process; IGI:MGI.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IMP:MGI.
DR GO; GO:0010667; P:negative regulation of cardiac muscle cell apoptotic process; ISO:MGI.
DR GO; GO:1903845; P:negative regulation of cellular response to transforming growth factor beta stimulus; ISO:MGI.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:MGI.
DR GO; GO:1904036; P:negative regulation of epithelial cell apoptotic process; ISO:MGI.
DR GO; GO:2001237; P:negative regulation of extrinsic apoptotic signaling pathway; IGI:MGI.
DR GO; GO:1902042; P:negative regulation of extrinsic apoptotic signaling pathway via death domain receptors; ISO:MGI.
DR GO; GO:1903944; P:negative regulation of hepatocyte apoptotic process; ISO:MGI.
DR GO; GO:1901740; P:negative regulation of myoblast fusion; IMP:BHF-UCL.
DR GO; GO:0060546; P:negative regulation of necroptotic process; IGI:MGI.
DR GO; GO:1903427; P:negative regulation of reactive oxygen species biosynthetic process; ISO:MGI.
DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISO:MGI.
DR GO; GO:1903055; P:positive regulation of extracellular matrix organization; ISO:MGI.
DR GO; GO:0072126; P:positive regulation of glomerular mesangial cell proliferation; ISO:MGI.
DR GO; GO:2000347; P:positive regulation of hepatocyte proliferation; ISO:MGI.
DR GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IMP:BHF-UCL.
DR GO; GO:0006508; P:proteolysis; IEA:InterPro.
DR GO; GO:0060544; P:regulation of necroptotic process; ISO:MGI.
DR GO; GO:0014842; P:regulation of skeletal muscle satellite cell proliferation; IMP:BHF-UCL.
DR GO; GO:0009617; P:response to bacterium; IEP:MGI.
DR GO; GO:0033574; P:response to testosterone; ISO:MGI.
DR GO; GO:0014732; P:skeletal muscle atrophy; IMP:BHF-UCL.
DR GO; GO:0007519; P:skeletal muscle tissue development; IMP:BHF-UCL.
DR GO; GO:0043403; P:skeletal muscle tissue regeneration; IMP:BHF-UCL.
DR GO; GO:0014866; P:skeletal myofibril assembly; IMP:BHF-UCL.
DR GO; GO:0042060; P:wound healing; IMP:BHF-UCL.
DR CDD; cd00032; CASc; 1.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR029030; Caspase-like_dom_sf.
DR InterPro; IPR011029; DEATH-like_dom_sf.
DR InterPro; IPR001875; DED_dom.
DR InterPro; IPR002398; Pept_C14.
DR InterPro; IPR001309; Pept_C14_p20.
DR InterPro; IPR015917; Pept_C14A.
DR PANTHER; PTHR10454; PTHR10454; 1.
DR Pfam; PF01335; DED; 2.
DR SMART; SM00115; CASc; 1.
DR SMART; SM00031; DED; 2.
DR SUPFAM; SSF47986; SSF47986; 2.
DR SUPFAM; SSF52129; SSF52129; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
DR PROSITE; PS50168; DED; 2.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Reference proteome; Repeat.
FT CHAIN 1..377
FT /note="CASP8 and FADD-like apoptosis regulator subunit p43"
FT /evidence="ECO:0000269|PubMed:31511692"
FT /id="PRO_0000004680"
FT CHAIN 378..481
FT /note="CASP8 and FADD-like apoptosis regulator subunit p12"
FT /evidence="ECO:0000269|PubMed:31511692"
FT /id="PRO_0000004681"
FT DOMAIN 6..78
FT /note="DED 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065"
FT DOMAIN 97..172
FT /note="DED 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00065"
FT REGION 6..307
FT /note="Interaction with CASP8 propeptide"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT REGION 6..229
FT /note="Interaction with FADD"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT REGION 6..200
FT /note="Interaction with CASP8"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT REGION 197..481
FT /note="Interaction with TRAF1 and TRAF2"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT REGION 197..436
FT /note="Interaction with CASP3"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT REGION 219..481
FT /note="Interaction with CASP8 subunits p18 and p10"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT REGION 265..360
FT /note="Caspase"
FT REGION 372..481
FT /note="Interaction with CASP8"
FT /evidence="ECO:0000250|UniProtKB:O15519"
FT SITE 371..372
FT /note="Cleavage; by CASP8"
FT /evidence="ECO:0000269|PubMed:31511692"
FT SITE 377..378
FT /note="Cleavage; by CASP8"
FT /evidence="ECO:0000269|PubMed:31511692"
FT VAR_SEQ 205..215
FT /note="LQNGRSKEPRF -> VSLEPVYGVPA (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9289491"
FT /id="VSP_000842"
FT VAR_SEQ 216..481
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:9289491"
FT /id="VSP_000843"
FT MUTAGEN 371
FT /note="D->A: Loss of CASP8-mediated cleavage; when
FT associated with A-377."
FT /evidence="ECO:0000269|PubMed:31511692"
FT MUTAGEN 377
FT /note="D->A: Loss of CASP8-mediated cleavage; when
FT associated with A-371."
FT /evidence="ECO:0000269|PubMed:31511692"
FT CONFLICT 121
FT /note="T -> TRIT (in Ref. 1; CAA74369/CAA74368)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 481 AA; 54875 MW; 433E07E2E5FA5A05 CRC64;
MAQSPVSAEV IHQVEECLDE DEKEMMLFLC RDVTENLAAP NVRDLLDSLS ERGQLSFATL
AELLYRVRRF DLLKRILKTD KATVEDHLRR NPHLVSDYRV LLMEIGESLD QNDVSSLVFL
TRDYTGRGKI AKDKSFLDLV IELEKLNLIA SDQLNLLEKC LKNIHRIDLN TKIQKYTQSS
QGARSNMNTL QASLPKLSIK YNSRLQNGRS KEPRFVEYRD SQRTLVKTSI QESGAFLPPH
IREETYRMQS KPLGICLIID CIGNDTKYLQ ETFTSLGYHI QLFLFPKSHD ITQIVRRYAS
MAQHQDYDSF ACVLVSLGGS QSMMGRDQVH SGFSLDHVKN MFTGDTCPSL RGKPKLFFIQ
NYESLGSQLE DSSLEVDGPS IKNVDSKPLQ PRHCTTHPEA DIFWSLCTAD VSHLEKPSSS
SSVYLQKLSQ QLKQGRRRPL VDLHVELMDK VYAWNSGVSS KEKYSLSLQH TLRKKLILAP
T
