TNFA_CEREL
ID TNFA_CEREL Reviewed; 229 AA.
AC P51743;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 104.
DE RecName: Full=Tumor necrosis factor;
DE AltName: Full=Cachectin;
DE AltName: Full=TNF-alpha;
DE AltName: Full=Tumor necrosis factor ligand superfamily member 2;
DE Short=TNF-a;
DE Contains:
DE RecName: Full=Tumor necrosis factor, membrane form;
DE AltName: Full=N-terminal fragment;
DE Short=NTF;
DE Contains:
DE RecName: Full=Intracellular domain 1;
DE Short=ICD1;
DE Contains:
DE RecName: Full=Intracellular domain 2;
DE Short=ICD2;
DE Contains:
DE RecName: Full=C-domain 1;
DE Contains:
DE RecName: Full=C-domain 2;
DE Contains:
DE RecName: Full=Tumor necrosis factor, soluble form;
DE Flags: Precursor; Fragment;
GN Name=TNF; Synonyms=TNFA, TNFSF2;
OS Cervus elaphus (Red deer).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Cervidae;
OC Cervinae; Cervus.
OX NCBI_TaxID=9860;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Lockhart E.A.;
RT "Cloning and sequencing of cervine tumor necrosis factor.";
RL Submitted (SEP-1994) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It
CC is mainly secreted by macrophages and can induce cell death of certain
CC tumor cell lines. It is potent pyrogen causing fever by direct action
CC or by stimulation of interleukin-1 secretion and is implicated in the
CC induction of cachexia, Under certain conditions it can stimulate cell
CC proliferation and induce cell differentiation (By similarity). Induces
CC insulin resistance in adipocytes via inhibition of insulin-induced IRS1
CC tyrosine phosphorylation and insulin-induced glucose uptake. Induces
CC GKAP42 protein degradation in adipocytes which is partially responsible
CC for TNF-induced insulin resistance (By similarity). Plays a role in
CC angiogenesis by inducing VEGF production synergistically with IL1B and
CC IL6 (By similarity). {ECO:0000250|UniProtKB:P01375,
CC ECO:0000250|UniProtKB:P06804}.
CC -!- FUNCTION: The TNF intracellular domain (ICD) form induces IL12
CC production in dendritic cells. {ECO:0000250|UniProtKB:P01375}.
CC -!- SUBUNIT: Homotrimer. Interacts with SPPL2B (By similarity).
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type II
CC membrane protein {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, membrane form]: Membrane
CC {ECO:0000250}; Single-pass type II membrane protein {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, soluble form]: Secreted
CC {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [C-domain 1]: Secreted {ECO:0000250}.
CC -!- SUBCELLULAR LOCATION: [C-domain 2]: Secreted {ECO:0000250}.
CC -!- PTM: The soluble form derives from the membrane form by proteolytic
CC processing. The membrane-bound form is further proteolytically
CC processed by SPPL2A or SPPL2B through regulated intramembrane
CC proteolysis producing TNF intracellular domains (ICD1 and ICD2)
CC released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into
CC the extracellular space (By similarity). {ECO:0000250}.
CC -!- PTM: The membrane form, but not the soluble form, is phosphorylated on
CC serine residues. Dephosphorylation of the membrane form occurs by
CC binding to soluble TNFRSF1A/TNFR1 (By similarity). {ECO:0000250}.
CC -!- PTM: O-glycosylated; glycans contain galactose, N-acetylgalactosamine
CC and N-acetylneuraminic acid. {ECO:0000250}.
CC -!- PTM: [Tumor necrosis factor, soluble form]: The soluble form is
CC demyristoylated by SIRT6, promoting its secretion.
CC {ECO:0000250|UniProtKB:P01375}.
CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}.
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DR EMBL; U14683; AAA50759.1; -; mRNA.
DR AlphaFoldDB; P51743; -.
DR SMR; P51743; -.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
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:0006955; P:immune response; IEA:InterPro.
DR GO; GO:0097527; P:necroptotic signaling pathway; ISS:CAFA.
DR GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; ISS:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISS:UniProtKB.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; ISS:UniProtKB.
DR GO; GO:0065008; P:regulation of biological quality; IEA:UniProt.
DR GO; GO:0050793; P:regulation of developmental process; IEA:UniProt.
DR GO; GO:0051046; P:regulation of secretion; IEA:UniProt.
DR GO; GO:0010573; P:vascular endothelial growth factor production; ISS:UniProtKB.
DR CDD; cd00184; TNF; 1.
DR Gene3D; 2.60.120.40; -; 1.
DR InterPro; IPR006053; TNF.
DR InterPro; IPR002959; TNF_alpha.
DR InterPro; IPR021184; TNF_CS.
DR InterPro; IPR006052; TNF_dom.
DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom.
DR PANTHER; PTHR11471:SF23; PTHR11471:SF23; 1.
DR Pfam; PF00229; TNF; 1.
DR PRINTS; PR01234; TNECROSISFCT.
DR PRINTS; PR01235; TNFALPHA.
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 Cell membrane; Cytokine; Disulfide bond; Glycoprotein; Lipoprotein;
KW Membrane; Myristate; Secreted; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN <1..229
FT /note="Tumor necrosis factor, membrane form"
FT /id="PRO_0000034415"
FT CHAIN <1..39
FT /note="Intracellular domain 1"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417211"
FT CHAIN <1..35
FT /note="Intracellular domain 2"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417212"
FT CHAIN 45..?
FT /note="C-domain 1"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417213"
FT CHAIN 47..?
FT /note="C-domain 2"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417214"
FT CHAIN 74..229
FT /note="Tumor necrosis factor, soluble form"
FT /id="PRO_0000034416"
FT TOPO_DOM <1..30
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 31..51
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 52..229
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT SITE 29..30
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 34..35
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 44..45
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 46..47
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 72..73
FT /note="Cleavage; by ADAM17"
FT /evidence="ECO:0000250"
FT LIPID 14
FT /note="N6-myristoyl lysine"
FT /evidence="ECO:0000250|UniProtKB:P01375"
FT LIPID 15
FT /note="N6-myristoyl lysine"
FT /evidence="ECO:0000250|UniProtKB:P01375"
FT CARBOHYD 76
FT /note="O-linked (GalNAc...) serine; in soluble form"
FT /evidence="ECO:0000250"
FT DISULFID 141..173
FT /evidence="ECO:0000250"
FT NON_TER 1
SQ SEQUENCE 229 AA; 24988 MW; 16DE5F7AA5A7DB35 CRC64;
MIRDVELAEE ALSKKAGGPQ GSRSCLCLSL FSFLLVAGAT TLFCLLHFGV IGPQREEQSP
TGLSINSPLV QTLRSSSQAS INKPVAHVVA NINAQGQLLW LDSCANALMA NGVKLEDNQL
VVPTDGLYLI YSQVLFRGQS CPSTPLFLTH TISRIAVSYQ TKVNILSAIK SPCHRETPEW
AEAKPWYEPI YQGGVFQLEK GDRLSAEINL PDYLDYAESG QVYFGIIAL
