TNFL6_RAT
ID TNFL6_RAT Reviewed; 278 AA.
AC P36940;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 03-AUG-2022, entry version 172.
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, Tnfsf6;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, AND INDUCTION.
RX PubMed=7505205; DOI=10.1016/0092-8674(93)90326-l;
RA Suda T., Takahashi T., Golstein P., Nagata S.;
RT "Molecular cloning and expression of the Fas ligand, a novel member of the
RT tumor necrosis factor family.";
RL Cell 75:1169-1178(1993).
CC -!- FUNCTION: Cytokine that binds to TNFRSF6/FAS, a receptor that
CC transduces the apoptotic signal into cells (PubMed:7505205). Involved
CC in cytotoxic T-cell-mediated apoptosis, natural killer cell-mediated
CC apoptosis and in T-cell development (PubMed:7505205). Initiates
CC fratricidal/suicidal activation-induced cell death (AICD) in antigen-
CC activated T-cells contributing to the termination of immune responses
CC (By similarity). TNFRSF6/FAS-mediated apoptosis has also a role in the
CC induction of peripheral tolerance (By similarity). Binds to
CC TNFRSF6B/DcR3, a decoy receptor that blocks apoptosis (By similarity).
CC {ECO:0000250|UniProtKB:P41047, ECO:0000250|UniProtKB:P48023,
CC ECO:0000269|PubMed:7505205}.
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. Can induce apoptosis but does not appear
CC to be essential for this process. {ECO:0000250|UniProtKB:P41047}.
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: Cell membrane {ECO:0000269|PubMed:7505205};
CC Single-pass type II membrane protein {ECO:0000255}. Cytoplasmic vesicle
CC lumen {ECO:0000250|UniProtKB:P48023}. Lysosome lumen
CC {ECO:0000250|UniProtKB:P48023}. Note=Colocalizes with the SPPL2A
CC protease at the cell membrane. Is internalized into multivesicular
CC bodies of secretory lysosomes after phosphorylation by FGR and
CC monoubiquitination. {ECO:0000250|UniProtKB:P48023}.
CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor ligand superfamily member
CC 6, soluble form]: Secreted {ECO:0000250|UniProtKB:P48023}. Note=May be
CC released into the extracellular fluid by cleavage from the cell
CC surface. {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 -!- TISSUE SPECIFICITY: Expressed in activated splenocytes and thymocytes.
CC Moderate or weak expression found in small intestines, kidney and lung.
CC {ECO:0000269|PubMed:7505205}.
CC -!- INDUCTION: By PMA/ionomycin and concanavalin/interleukin-2.
CC {ECO:0000269|PubMed:7505205}.
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. {ECO:0000250|UniProtKB:P48023}.
CC -!- PTM: Monoubiquitinated. {ECO:0000250|UniProtKB:P48023}.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
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DR EMBL; U03470; AAC52129.1; -; mRNA.
DR PIR; A49266; A49266.
DR RefSeq; NP_037040.1; NM_012908.1.
DR RefSeq; XP_006250210.1; XM_006250148.3.
DR RefSeq; XP_008767829.1; XM_008769607.2.
DR RefSeq; XP_017454164.1; XM_017598675.1.
DR AlphaFoldDB; P36940; -.
DR SMR; P36940; -.
DR STRING; 10116.ENSRNOP00000003998; -.
DR GlyGen; P36940; 3 sites.
DR PhosphoSitePlus; P36940; -.
DR PaxDb; P36940; -.
DR PRIDE; P36940; -.
DR Ensembl; ENSRNOT00000003998; ENSRNOP00000003998; ENSRNOG00000002978.
DR GeneID; 25385; -.
DR KEGG; rno:25385; -.
DR UCSC; RGD:3880; rat.
DR CTD; 356; -.
DR RGD; 3880; Faslg.
DR eggNOG; ENOG502RXC1; Eukaryota.
DR GeneTree; ENSGT01050000244957; -.
DR HOGENOM; CLU_070352_2_0_1; -.
DR InParanoid; P36940; -.
DR OMA; YPQIFWV; -.
DR OrthoDB; 1029363at2759; -.
DR PhylomeDB; P36940; -.
DR TreeFam; TF332169; -.
DR Reactome; R-RNO-3371378; Regulation by c-FLIP.
DR Reactome; R-RNO-5218900; CASP8 activity is inhibited.
DR Reactome; R-RNO-69416; Dimerization of procaspase-8.
DR Reactome; R-RNO-75157; FasL/ CD95L signaling.
DR PRO; PR:P36940; -.
DR Proteomes; UP000002494; Chromosome 13.
DR Bgee; ENSRNOG00000002978; Expressed in ileum and 8 other tissues.
DR ExpressionAtlas; P36940; baseline and differential.
DR Genevisible; P36940; RN.
DR GO; GO:0005901; C:caveola; IDA:RGD.
DR GO; GO:0009986; C:cell surface; ISO:RGD.
DR GO; GO:0031410; C:cytoplasmic vesicle; IDA:RGD.
DR GO; GO:0060205; C:cytoplasmic vesicle lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; ISO:RGD.
DR GO; GO:0070062; C:extracellular exosome; ISO:RGD.
DR GO; GO:0005615; C:extracellular space; ISO:RGD.
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; IDA:RGD.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005123; F:death receptor binding; IPI:RGD.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IMP:RGD.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; ISO:RGD.
DR GO; GO:0097190; P:apoptotic signaling pathway; ISO:RGD.
DR GO; GO:0030644; P:cellular chloride ion homeostasis; IDA:RGD.
DR GO; GO:0071346; P:cellular response to interferon-gamma; IEP:RGD.
DR GO; GO:0048388; P:endosomal lumen acidification; IDA:RGD.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; ISO:RGD.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IMP:RGD.
DR GO; GO:0006925; P:inflammatory cell apoptotic process; IGI:RGD.
DR GO; GO:0070266; P:necroptotic process; ISO:RGD.
DR GO; GO:0097527; P:necroptotic signaling pathway; ISO:RGD.
DR GO; GO:0016525; P:negative regulation of angiogenesis; ISO:RGD.
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:RGD.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:RGD.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; ISO:RGD.
DR GO; GO:0045742; P:positive regulation of epidermal growth factor receptor signaling pathway; IMP:RGD.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISO:RGD.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IMP:RGD.
DR GO; GO:1905782; P:positive regulation of phosphatidylserine exposure on apoptotic cell surface; ISO:RGD.
DR GO; GO:1903514; P:release of sequestered calcium ion into cytosol by endoplasmic reticulum; ISO:RGD.
DR GO; GO:0070848; P:response to growth factor; IEP:RGD.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEP:RGD.
DR GO; GO:0046666; P:retinal cell programmed cell death; ISO:RGD.
DR GO; GO:0070231; P:T cell apoptotic process; ISO:RGD.
DR CDD; cd00184; TNF; 1.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR028326; FASL.
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 SMART; SM00207; TNF; 1.
DR SUPFAM; SSF49842; SSF49842; 1.
DR PROSITE; PS00251; TNF_1; 1.
DR PROSITE; PS50049; TNF_2; 1.
PE 2: Evidence at transcript level;
KW Apoptosis; Cell membrane; Cytokine; Cytoplasmic vesicle; Disulfide bond;
KW Glycoprotein; Lysosome; Membrane; Nucleus; Reference proteome; Repressor;
KW Secreted; Signal-anchor; Transcription; Transcription regulation;
KW Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..278
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT membrane form"
FT /id="PRO_0000034512"
FT CHAIN 1..126
FT /note="ADAM10-processed FasL form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417163"
FT CHAIN 1..79
FT /note="FasL intracellular domain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417164"
FT CHAIN 127..278
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT soluble form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000034513"
FT TOPO_DOM 1..77
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 78..99
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 100..278
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 26..68
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 125..147
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 39..68
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 125..142
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 78..79
FT /note="Cleavage; by SPPL2A"
FT /evidence="ECO:0000250"
FT SITE 126..127
FT /note="Cleavage; by ADAM10"
FT /evidence="ECO:0000250"
FT CARBOHYD 116
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 247
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 257
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 199..230
FT /evidence="ECO:0000250|UniProtKB:P48023"
SQ SEQUENCE 278 AA; 31140 MW; 2898E18A862CEAC6 CRC64;
MQQPVNYPCP QIYWVDSSAT SPWAPPGSVF SCPSSGPRGP GQRRPPPPPP PPSPLPPPSQ
PPPLPPLSPL KKKDNIELWL PVIFFMVLVA LVGMGLGMYQ LFHLQKELAE LREFTNHSLR
VSSFEKQIAN PSTPSETKKP RSVAHLTGNP RSRSIPLEWE DTYGTALISG VKYKKGGLVI
NEAGLYFVYS KVYFRGQSCN SQPLSHKVYM RNFKYPGDLV LMEEKKLNYC TTGQIWAHSS
YLGAVFNLTV ADHLYVNISQ LSLINFEESK TFFGLYKL
