TNFL6_MOUSE
ID TNFL6_MOUSE Reviewed; 279 AA.
AC P41047; Q61217; Q9R1F2;
DT 01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 1.
DT 03-AUG-2022, entry version 202.
DE RecName: Full=Tumor necrosis factor ligand superfamily member 6;
DE AltName: Full=CD95 ligand;
DE Short=CD95-L;
DE AltName: Full=Fas antigen ligand;
DE Short=Fas ligand;
DE Short=FasL;
DE AltName: CD_antigen=CD178;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 6, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor ligand superfamily member 6, soluble form;
DE AltName: Full=Receptor-binding FasL ectodomain;
DE AltName: Full=Soluble Fas ligand;
DE Short=sFasL;
DE Contains:
DE RecName: Full=ADAM10-processed FasL form;
DE Short=APL;
DE Contains:
DE RecName: Full=FasL intracellular domain;
DE Short=FasL ICD;
DE AltName: Full=SPPL2A-processed FasL form;
DE Short=SPA;
GN Name=Faslg; Synonyms=Apt1lg1, Cd95l, Fasl, gld, Tnfsf6;
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] (ISOFORM FASL), AND FUNCTION.
RX PubMed=7511063; DOI=10.1016/0092-8674(94)90375-1;
RA Takahashi T., Tanaka M., Brannan C.I., Jenkins N.A., Copeland N.G.,
RA Suda T., Nagata S.;
RT "Generalized lymphoproliferative disease in mice, caused by a point
RT mutation in the Fas ligand.";
RL Cell 76:969-976(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL), AND 3D-STRUCTURE MODELING.
RC STRAIN=C57BL/6J;
RX PubMed=7544870; DOI=10.1016/0161-5890(95)00016-8;
RA Peitsch M.C., Tschopp J.;
RT "Comparative molecular modelling of the Fas-ligand and other members of the
RT TNF family.";
RL Mol. Immunol. 32:761-772(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL).
RX PubMed=7889405; DOI=10.1016/1074-7613(94)90106-6;
RA Lynch D.H., Watson M.L., Alderson M.R., Baum P.R., Miller R.E., Tough T.,
RA Gibson M., Davis-Smith T., Smith C.A., Hunter K.;
RT "The mouse Fas-ligand gene is mutated in gld mice and is part of a TNF
RT family gene cluster.";
RL Immunity 1:131-136(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASL).
RC STRAIN=BALB/cJ;
RA Fenner M.H., Shioda T., Isselbacher K.J.;
RT "Mus musculus Balb/c Fas ligand differs from 129/SV Fas ligand in two amino
RT acids.";
RL Submitted (MAY-1996) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM FASLS), AND SUBCELLULAR LOCATION.
RC STRAIN=C3H/HeJ; TISSUE=Spleen;
RX PubMed=10552956;
RA Ayroldi E., D'Adamio F., Zollo O., Agostini M., Moraca R., Cannarile L.,
RA Migliorati G., Delfino D.V., Riccardi C.;
RT "Cloning and expression of a short Fas ligand: a new alternatively spliced
RT product of the mouse Fas ligand gene.";
RL Blood 94:3456-3467(1999).
RN [6]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=7532682; DOI=10.1084/jem.181.3.1235;
RA Arase H., Arase N., Saito T.;
RT "Fas-mediated cytotoxicity by freshly isolated natural killer cells.";
RL J. Exp. Med. 181:1235-1238(1995).
RN [7]
RP FUNCTION.
RX PubMed=10779162; DOI=10.1089/10430340050015464;
RA Georgantas R.W. III, Leong K.W., August J.T.;
RT "Antigen-specific induction of peripheral T cell tolerance in vivo by
RT codelivery of DNA vectors encoding antigen and Fas ligand.";
RL Hum. Gene Ther. 11:851-858(2000).
RN [8]
RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=19794494; DOI=10.1038/nature08402;
RA O'Reilly L.A., Tai L., Lee L., Kruse E.A., Grabow S., Fairlie W.D.,
RA Haynes N.M., Tarlinton D.M., Zhang J.G., Belz G.T., Smyth M.J.,
RA Bouillet P., Robb L., Strasser A.;
RT "Membrane-bound Fas ligand only is essential for Fas-induced apoptosis.";
RL Nature 461:659-663(2009).
RN [9]
RP CHARACTERIZATION OF VARIANT GLD.
RX PubMed=7495745; DOI=10.1093/intimm/7.9.1381;
RA Hahne M., Peitsch M.C., Irmler M., Schroeter M., Lowin B., Rousseau M.,
RA Bron C., Renno T., French L., Tschopp J.;
RT "Characterization of the non-functional Fas ligand of gld mice.";
RL Int. Immunol. 7:1381-1386(1995).
RN [10]
RP VARIANTS ALA-184 AND GLY-218.
RC STRAIN=BALB/cJ, C3H/HeJ, C57BL/6J, DBA/1, DBA/2J, MRL/MpJ, NOD, NZB,
RC NZW/LacJ, and SJL/J;
RX PubMed=9108079; DOI=10.1073/pnas.94.8.3914;
RA Kayagaki N., Yamaguchi N., Nagao F., Matsuo S., Maeda H., Okumura K.,
RA Yagita H.;
RT "Polymorphism of murine Fas ligand that affects the biological activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:3914-3919(1997).
CC -!- FUNCTION: Cytokine that binds to TNFRSF6/FAS, a receptor that
CC transduces the apoptotic signal into cells (PubMed:7511063). Involved
CC in cytotoxic T-cell-mediated apoptosis, natural killer cell-mediated
CC apoptosis and in T-cell development (PubMed:19794494, PubMed:7532682).
CC Initiates fratricidal/suicidal activation-induced cell death (AICD) in
CC antigen-activated T-cells contributing to the termination of immune
CC responses (PubMed:19794494). TNFRSF6/FAS-mediated apoptosis has also a
CC role in the induction of peripheral tolerance (PubMed:10779162). Binds
CC to TNFRSF6B/DcR3, a decoy receptor that blocks apoptosis (By
CC similarity). {ECO:0000250|UniProtKB:P48023,
CC ECO:0000269|PubMed:19794494, ECO:0000269|PubMed:7511063,
CC ECO:0000269|PubMed:7532682}.
CC -!- FUNCTION: [Tumor necrosis factor ligand superfamily member 6, soluble
CC form]: Induces FAS-mediated activation of NF-kappa-B, initiating non-
CC apoptotic signaling pathways (PubMed:19794494). Can induce apoptosis
CC but does not appear to be essential for this process (By similarity).
CC {ECO:0000250|UniProtKB:P48023, ECO:0000269|PubMed:19794494}.
CC -!- FUNCTION: [FasL intracellular domain]: Cytoplasmic form induces gene
CC transcription inhibition. {ECO:0000250|UniProtKB:P48023}.
CC -!- SUBUNIT: Homotrimer. Interacts with ARHGAP9, BAIAP2L1, BTK, CACNB3,
CC CACNB4, CRK, DLG2, DNMBP, DOCK4, EPS8L3, FGR, FYB1, FYN, HCK, ITK,
CC ITSN2, KALRN, LYN, MACC1, MIA, MPP4, MYO15A, NCF1, NCK1, NCK2, NCKIPSD,
CC OSTF1, PIK3R1, PSTPIP1, RIMBP3C, SAMSN1, SH3GL3, SH3PXD2B, SH3PXD2A,
CC SH3RF2, SKAP2, SNX33, SNX9, SORBS3, SPTA1, SRC, SRGAP1, SRGAP2, SRGAP3,
CC TEC, TJP3 and YES1. {ECO:0000250|UniProtKB:P48023}.
CC -!- SUBCELLULAR LOCATION: [Isoform FasL]: Cell membrane
CC {ECO:0000269|PubMed:19794494, ECO:0000269|PubMed:7532682}; Single-pass
CC type II membrane protein {ECO:0000255}. Cytoplasmic vesicle lumen
CC {ECO:0000250|UniProtKB:P48023}. Lysosome lumen
CC {ECO:0000250|UniProtKB:P48023}. Note=Is internalized into
CC multivesicular bodies of secretory lysosomes after phosphorylation by
CC FGR and monoubiquitination. Colocalizes with the SPPL2A protease at the
CC cell membrane. {ECO:0000250|UniProtKB:P48023}.
CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor ligand superfamily member
CC 6, soluble form]: Secreted {ECO:0000269|PubMed:10552956,
CC ECO:0000269|PubMed:19794494}. Note=May be released into the
CC extracellular fluid by cleavage from the cell surface.
CC {ECO:0000250|UniProtKB:P48023}.
CC -!- SUBCELLULAR LOCATION: [FasL intracellular domain]: Nucleus
CC {ECO:0000250|UniProtKB:P48023}. Note=The FasL ICD cytoplasmic form is
CC translocated into the nucleus. {ECO:0000250|UniProtKB:P48023}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=FasL;
CC IsoId=P41047-1; Sequence=Displayed;
CC Name=FasLS;
CC IsoId=P41047-2; Sequence=VSP_006445;
CC -!- TISSUE SPECIFICITY: Expressed in T-cells (PubMed:19794494). Expressed
CC in natural killer cells (PubMed:7532682). {ECO:0000269|PubMed:19794494,
CC ECO:0000269|PubMed:7532682}.
CC -!- PTM: The soluble form derives from the membrane form by proteolytic
CC processing. The membrane-bound form undergoes two successive
CC intramembrane proteolytic cleavages. The first one is processed by
CC ADAM10 producing an N-terminal fragment, which lacks the receptor-
CC binding extracellular domain. This ADAM10-processed FasL (FAsL APL)
CC remnant form is still membrane anchored and further processed by SPPL2A
CC that liberates the FasL intracellular domain (FasL ICD). FasL shedding
CC by ADAM10 is a prerequisite for subsequent intramembrane cleavage by
CC SPPL2A in T-cells. {ECO:0000250|UniProtKB:P48023}.
CC -!- PTM: Phosphorylated by FGR on tyrosine residues; this is required for
CC ubiquitination and subsequent internalization.
CC {ECO:0000250|UniProtKB:P48023}.
CC -!- PTM: N-glycosylated. Glycosylation enhances apoptotic activity.
CC {ECO:0000250|UniProtKB:P48023}.
CC -!- PTM: Monoubiquitinated. {ECO:0000250|UniProtKB:P48023}.
CC -!- DISEASE: Note=A deficiency in this protein is the cause of generalized
CC lymphoproliferation disease phenotype (gld). Gld mice present
CC lymphadenopathy and autoantibody production. The phenotype is
CC recessively inherited. {ECO:0000269|PubMed:7511063}.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
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DR EMBL; U06948; AAA17800.1; -; mRNA.
DR EMBL; U10984; AAA19778.1; -; mRNA.
DR EMBL; S76752; AAB33780.1; -; mRNA.
DR EMBL; U58995; AAB02915.1; -; mRNA.
DR EMBL; AF119335; AAD52106.1; -; mRNA.
DR CCDS; CCDS15418.1; -. [P41047-1]
DR PIR; A53062; A53062.
DR RefSeq; NP_034307.1; NM_010177.4. [P41047-1]
DR AlphaFoldDB; P41047; -.
DR SMR; P41047; -.
DR BioGRID; 199595; 2.
DR MINT; P41047; -.
DR STRING; 10090.ENSMUSP00000000834; -.
DR GlyGen; P41047; 4 sites.
DR PhosphoSitePlus; P41047; -.
DR PaxDb; P41047; -.
DR PRIDE; P41047; -.
DR Antibodypedia; 4418; 1329 antibodies from 46 providers.
DR DNASU; 14103; -.
DR Ensembl; ENSMUST00000000834; ENSMUSP00000000834; ENSMUSG00000000817. [P41047-1]
DR Ensembl; ENSMUST00000193648; ENSMUSP00000141422; ENSMUSG00000000817. [P41047-2]
DR GeneID; 14103; -.
DR KEGG; mmu:14103; -.
DR UCSC; uc007dfr.2; mouse. [P41047-1]
DR CTD; 14103; -.
DR MGI; MGI:99255; Fasl.
DR VEuPathDB; HostDB:ENSMUSG00000000817; -.
DR eggNOG; ENOG502RXC1; Eukaryota.
DR GeneTree; ENSGT01050000244957; -.
DR HOGENOM; CLU_070352_2_0_1; -.
DR InParanoid; P41047; -.
DR OMA; YPQIFWV; -.
DR PhylomeDB; P41047; -.
DR TreeFam; TF332169; -.
DR Reactome; R-MMU-3371378; Regulation by c-FLIP.
DR Reactome; R-MMU-5218900; CASP8 activity is inhibited.
DR Reactome; R-MMU-69416; Dimerization of procaspase-8.
DR Reactome; R-MMU-75157; FasL/ CD95L signaling.
DR BioGRID-ORCS; 14103; 1 hit in 74 CRISPR screens.
DR ChiTaRS; Fasl; mouse.
DR PRO; PR:P41047; -.
DR Proteomes; UP000000589; Chromosome 1.
DR RNAct; P41047; protein.
DR Bgee; ENSMUSG00000000817; Expressed in ectoplacental cone and 24 other tissues.
DR ExpressionAtlas; P41047; baseline and differential.
DR Genevisible; P41047; MM.
DR GO; GO:0005901; C:caveola; ISO:MGI.
DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL.
DR GO; GO:0031410; C:cytoplasmic vesicle; ISO:MGI.
DR GO; GO:0060205; C:cytoplasmic vesicle lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR GO; GO:0070062; C:extracellular exosome; ISO:MGI.
DR GO; GO:0005615; C:extracellular space; ISO:MGI.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043202; C:lysosomal lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0045121; C:membrane raft; ISO:MGI.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISO:MGI.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005123; F:death receptor binding; ISO:MGI.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; ISO:MGI.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:MGI.
DR GO; GO:0097190; P:apoptotic signaling pathway; IDA:MGI.
DR GO; GO:0030644; P:cellular chloride ion homeostasis; ISO:MGI.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEA:Ensembl.
DR GO; GO:0048388; P:endosomal lumen acidification; ISO:MGI.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISO:MGI.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:MGI.
DR GO; GO:0006925; P:inflammatory cell apoptotic process; ISO:MGI.
DR GO; GO:0070266; P:necroptotic process; ISO:MGI.
DR GO; GO:0097527; P:necroptotic signaling pathway; ISO:MGI.
DR GO; GO:0016525; P:negative regulation of angiogenesis; ISO:MGI.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; ISO:MGI.
DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; ISO:MGI.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:1905782; P:positive regulation of phosphatidylserine exposure on apoptotic cell surface; ISO:MGI.
DR GO; GO:1903514; P:release of sequestered calcium ion into cytosol by endoplasmic reticulum; ISO:MGI.
DR GO; GO:0070848; P:response to growth factor; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0046666; P:retinal cell programmed cell death; IMP:MGI.
DR GO; GO:0070231; P:T cell apoptotic process; ISO:MGI.
DR CDD; cd00184; TNF; 1.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR028326; FASL.
DR InterPro; IPR006053; TNF.
DR InterPro; IPR021184; TNF_CS.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR Pfam; PF00229; TNF; 1.
DR PRINTS; PR01681; FASLIGAND.
DR PRINTS; PR01234; TNECROSISFCT.
DR SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS00251; TNF_1; 1.
DR PROSITE; PS50049; TNF_2; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Apoptosis; Cell membrane; Cytokine;
KW Cytoplasmic vesicle; Disease variant; Disulfide bond; Glycoprotein;
KW Lysosome; Membrane; Nucleus; Reference proteome; Repressor; Secreted;
KW Signal-anchor; Transcription; Transcription regulation; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1..279
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT membrane form"
FT /id="PRO_0000034508"
FT CHAIN 1..127
FT /note="ADAM10-processed FasL form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417159"
FT CHAIN 1..80
FT /note="FasL intracellular domain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417160"
FT CHAIN 128..279
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT soluble form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000034509"
FT TOPO_DOM 1..78
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 79..100
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 101..279
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 30..70
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 126..150
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 30..68
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 79..80
FT /note="Cleavage; by SPPL2A"
FT /evidence="ECO:0000250"
FT SITE 127..128
FT /note="Cleavage; by ADAM10"
FT /evidence="ECO:0000250"
FT CARBOHYD 117
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 182
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 248
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 258
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 200..231
FT /evidence="ECO:0000250|UniProtKB:P48023"
FT VAR_SEQ 1..210
FT /note="Missing (in isoform FasLS)"
FT /evidence="ECO:0000303|PubMed:10552956"
FT /id="VSP_006445"
FT VARIANT 184
FT /note="T -> A (in strain: BALB/c, DBA/1 and DBA/2; enhances
FT cytotoxicity)"
FT /evidence="ECO:0000269|PubMed:9108079"
FT VARIANT 218
FT /note="E -> G (in strain: BALB/c, DBA/1 and DBA/2; enhances
FT cytotoxicity)"
FT /evidence="ECO:0000269|PubMed:9108079"
FT VARIANT 273
FT /note="F -> L (in gld; abolishes binding of FASL to its
FT receptor)"
SQ SEQUENCE 279 AA; 31442 MW; 37972E2728E0A1CA CRC64;
MQQPMNYPCP QIFWVDSSAT SSWAPPGSVF PCPSCGPRGP DQRRPPPPPP PVSPLPPPSQ
PLPLPPLTPL KKKDHNTNLW LPVVFFMVLV ALVGMGLGMY QLFHLQKELA ELREFTNQSL
KVSSFEKQIA NPSTPSEKKE PRSVAHLTGN PHSRSIPLEW EDTYGTALIS GVKYKKGGLV
INETGLYFVY SKVYFRGQSC NNQPLNHKVY MRNSKYPEDL VLMEEKRLNY CTTGQIWAHS
SYLGAVFNLT SADHLYVNIS QLSLINFEES KTFFGLYKL
