TNFL6_MACNE
ID TNFL6_MACNE Reviewed; 280 AA.
AC P63306; Q9BDM5; Q9MYL6;
DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT 11-OCT-2004, sequence version 1.
DT 03-AUG-2022, entry version 99.
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=CD95L, FASL, TNFSF6;
OS Macaca nemestrina (Pig-tailed macaque).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Macaca.
OX NCBI_TaxID=9545;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=12957408; DOI=10.1016/s0022-1759(03)00187-x;
RA Kirii Y., Inoue T., Yoshino K., Kayagaki N., Yagita H., Okumura K.,
RA Shibata H., Yoshikawa Y., Terao K.;
RT "Molecular cloning, functional characterization, and enzyme-linked
RT immunosorbent assay of cynomolgus monkey Fas ligand.";
RL J. Immunol. Methods 278:201-209(2003).
CC -!- FUNCTION: Cytokine that binds to TNFRSF6/FAS, a receptor that
CC transduces the apoptotic signal into cells. Involved in cytotoxic T-
CC cell-mediated apoptosis, natural killer cell-mediated apoptosis and in
CC T-cell development. Initiates fratricidal/suicidal activation-induced
CC cell death (AICD) in antigen-activated T-cells contributing to the
CC termination of immune responses. TNFRSF6/FAS-mediated apoptosis has
CC also a role in the induction of peripheral tolerance. Binds to
CC TNFRSF6B/DcR3, a decoy receptor that blocks apoptosis.
CC {ECO:0000250|UniProtKB:P41047, ECO:0000250|UniProtKB:P48023}.
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:0000250|UniProtKB:P48023};
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 form 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 -!- 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 -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
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DR EMBL; AB035140; BAA90296.1; -; mRNA.
DR RefSeq; NP_001292845.1; NM_001305916.1.
DR AlphaFoldDB; P63306; -.
DR SMR; P63306; -.
DR STRING; 9545.ENSMNEP00000034549; -.
DR Ensembl; ENSMNET00000058999; ENSMNEP00000034549; ENSMNEG00000040462.
DR GeneID; 105484428; -.
DR CTD; 356; -.
DR GeneTree; ENSGT01050000244957; -.
DR OMA; YPQIFWV; -.
DR OrthoDB; 1029363at2759; -.
DR Proteomes; UP000233120; Unplaced.
DR Bgee; ENSMNEG00000040462; Expressed in lymph node and 2 other tissues.
DR GO; GO:0060205; C:cytoplasmic vesicle lumen; IEA:UniProtKB-SubCell.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0070062; C:extracellular exosome; IEA:Ensembl.
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:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl.
DR GO; GO:0006955; P:immune response; IEA:InterPro.
DR GO; GO:0097527; P:necroptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0016525; P:negative regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISS:UniProtKB.
DR GO; GO:2000353; P:positive regulation of endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:1905782; P:positive regulation of phosphatidylserine exposure on apoptotic cell surface; IEA:Ensembl.
DR GO; GO:1903514; P:release of sequestered calcium ion into cytosol by endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0046666; P:retinal cell programmed cell death; IEA:Ensembl.
DR GO; GO:0070231; P:T cell apoptotic process; IEA:Ensembl.
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 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..280
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT membrane form"
FT /id="PRO_0000034506"
FT CHAIN 1..128
FT /note="ADAM10-processed FasL form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417157"
FT CHAIN 1..81
FT /note="FasL intracellular domain"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417158"
FT CHAIN 129..280
FT /note="Tumor necrosis factor ligand superfamily member 6,
FT soluble form"
FT /evidence="ECO:0000250"
FT /id="PRO_0000034507"
FT TOPO_DOM 1..80
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 81..101
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 102..280
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT REGION 20..70
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 117..155
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 26..70
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 133..148
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 80..81
FT /note="Cleavage; by SPPL2A"
FT /evidence="ECO:0000250"
FT SITE 128..129
FT /note="Cleavage; by ADAM10"
FT /evidence="ECO:0000250"
FT CARBOHYD 183
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 249
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 259
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 201..232
FT /evidence="ECO:0000250|UniProtKB:P48023"
SQ SEQUENCE 280 AA; 31368 MW; F0B284D61A132EB4 CRC64;
MQQPFNYPYP QIYWVDSSAS SPWAPPGTVL PCPTSVPRRP GQRRPPPPPP PPPLPPPPPS
PLPPLPLPPL KKRGNHSTGL CLLVMFFMVL VALVGLGLGM FQLFHLQKEL AELRESTSQK
HTASSLEKQI GHPSPPPEKK EQRKVAHLTG KPNSRSMPLE WEDTYGIVLL SGVKYKKGGL
VINETGLYFV YSKVYFRGQS CTNLPLSHKV YMRNSKYPQD LVMMEGKMMS YCTTGQMWAH
SSYLGAVFNL TSADHLYVNV SELSLVNFEE SQTFFGLYKL
