TNFA_BOVIN
ID TNFA_BOVIN Reviewed; 234 AA.
AC Q06599; A4IFT5; A9QWR7; O18779; Q27978;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 26-JUN-2007, sequence version 2.
DT 03-AUG-2022, entry version 175.
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;
GN Name=TNF; Synonyms=TNFA, TNFSF2;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2).
RX PubMed=8260599; DOI=10.1016/1043-4666(93)90065-d;
RA Cludts I., Cleuter Y., Kettmann R., Burny A., Droogmans L.;
RT "Cloning and characterization of the tandemly arranged bovine lymphotoxin
RT and tumour necrosis factor-alpha genes.";
RL Cytokine 5:336-341(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2).
RC STRAIN=Boran, and N'Dama;
RA Iraqi F.;
RT "Bovine TNF-alpha gene.";
RL Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA Ahn J.;
RL Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC STRAIN=Belted Galloway; TISSUE=Peripheral blood;
RG U.S. Veterinary Immune Reagent Network;
RA Hudgens T., Tompkins D., Baldwin C.L.;
RT "U.S. veterinary immune reagent network: expressed bovine gene sequences.";
RL Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC STRAIN=Hereford; TISSUE=Thymus;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 50-233 (ISOFORM 1).
RC TISSUE=Blood;
RX PubMed=7590981; DOI=10.1007/bf00179409;
RA Mertens B.E.L.C., Muriuki M., Gaidulis L.;
RT "Cloning of two members of the TNF-superfamily in cattle: CD40 ligand and
RT tumor necrosis factor alpha.";
RL Immunogenetics 42:430-431(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 91-193.
RC STRAIN=Holstein;
RX PubMed=9303477; DOI=10.2527/1997.7592567x;
RA Dietz A.B., Neibergs H.L., Womack J.E., Kehrli M.E. Jr.;
RT "Rapid communication: single strand conformational polymorphism (SSCP) of
RT bovine tumor necrosis factor alpha.";
RL J. Anim. Sci. 75:2567-2567(1997).
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 -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q06599-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q06599-2; Sequence=VSP_026198;
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}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA19573.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; Z14137; CAA78511.1; -; Genomic_DNA.
DR EMBL; AF011926; AAB84086.1; -; Genomic_DNA.
DR EMBL; AF011927; AAB84087.1; -; Genomic_DNA.
DR EMBL; AF348421; AAN76506.1; -; mRNA.
DR EMBL; EU276079; ABX72077.1; -; mRNA.
DR EMBL; BC134755; AAI34756.1; -; mRNA.
DR EMBL; Z48808; CAA88743.1; -; mRNA.
DR EMBL; U11040; AAA19573.1; ALT_SEQ; Genomic_DNA.
DR PIR; I46047; S24642.
DR RefSeq; NP_776391.2; NM_173966.3. [Q06599-1]
DR RefSeq; XP_005223653.3; XM_005223596.3. [Q06599-2]
DR AlphaFoldDB; Q06599; -.
DR SMR; Q06599; -.
DR STRING; 9913.ENSBTAP00000035682; -.
DR PaxDb; Q06599; -.
DR PRIDE; Q06599; -.
DR GeneID; 280943; -.
DR KEGG; bta:280943; -.
DR CTD; 7124; -.
DR eggNOG; ENOG502S4K8; Eukaryota.
DR HOGENOM; CLU_070352_3_1_1; -.
DR InParanoid; Q06599; -.
DR OrthoDB; 1124938at2759; -.
DR TreeFam; TF332169; -.
DR Proteomes; UP000009136; Unplaced.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0005615; C:extracellular space; IDA:AgBase.
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; IBA:GO_Central.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IBA:GO_Central.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IBA:GO_Central.
DR GO; GO:0006955; P:immune response; IEA:InterPro.
DR GO; GO:0097527; P:necroptotic signaling pathway; ISS:CAFA.
DR GO; GO:2000252; P:negative regulation of feeding behavior; IMP:AgBase.
DR GO; GO:1903488; P:negative regulation of lactation; IMP:AgBase.
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:2001238; P:positive regulation of extrinsic apoptotic signaling pathway; IBA:GO_Central.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IBA:GO_Central.
DR GO; GO:0050729; P:positive regulation of inflammatory response; IMP:AgBase.
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:0010756; P:positive regulation of plasminogen activation; IMP:AgBase.
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:0045944; P:positive regulation of transcription by RNA polymerase II; IBA:GO_Central.
DR GO; GO:0090208; P:positive regulation of triglyceride metabolic process; IMP:AgBase.
DR GO; GO:0002532; P:production of molecular mediator involved in inflammatory response; IMP:AgBase.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IBA:GO_Central.
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 Alternative splicing; Cell membrane; Cytokine; Disulfide bond;
KW Glycoprotein; Lipoprotein; Membrane; Myristate; Phosphoprotein;
KW Reference proteome; Secreted; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..234
FT /note="Tumor necrosis factor, membrane form"
FT /id="PRO_0000034403"
FT CHAIN 1..39
FT /note="Intracellular domain 1"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417179"
FT CHAIN 1..35
FT /note="Intracellular domain 2"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417180"
FT CHAIN 50..?
FT /note="C-domain 1"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417181"
FT CHAIN 52..?
FT /note="C-domain 2"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417182"
FT CHAIN 78..234
FT /note="Tumor necrosis factor, soluble form"
FT /id="PRO_0000034404"
FT TOPO_DOM 1..35
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 36..56
FT /note="Helical; Signal-anchor for type II membrane protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 57..234
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT SITE 34..35
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 39..40
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 49..50
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 51..52
FT /note="Cleavage; by SPPL2A or SPPL2B"
FT /evidence="ECO:0000250"
FT SITE 77..78
FT /note="Cleavage; by ADAM17"
FT /evidence="ECO:0000250"
FT MOD_RES 2
FT /note="Phosphoserine; by CK1"
FT /evidence="ECO:0000250"
FT LIPID 20
FT /note="N6-myristoyl lysine"
FT /evidence="ECO:0000250|UniProtKB:P01375"
FT CARBOHYD 81
FT /note="O-linked (GalNAc...) serine; in soluble form"
FT /evidence="ECO:0000250"
FT DISULFID 146..178
FT /evidence="ECO:0000250"
FT VAR_SEQ 63
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.4"
FT /id="VSP_026198"
FT VARIANT 48
FT /note="F -> C (in strain: N'Dama)"
FT CONFLICT 114
FT /note="M -> V (in Ref. 3; AAN76506)"
FT /evidence="ECO:0000305"
FT CONFLICT 167
FT /note="K -> R (in Ref. 3; AAN76506)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 234 AA; 25567 MW; BAE4D0CD3797F491 CRC64;
MSTKSMIRDV ELAEEVLSEK AGGPQGSRSC LCLSLFSFLL VAGATTLFCL LHFGVIGPQR
EEQSPGGPSI NSPLVQTLRS SSQASSNKPV AHVVADINSP GQLRWWDSYA NALMANGVKL
EDNQLVVPAD GLYLIYSQVL FRGQGCPSTP LFLTHTISRI AVSYQTKVNI LSAIKSPCHR
ETPEWAEAKP WYEPIYQGGV FQLEKGDRLS AEINLPDYLD YAESGQVYFG IIAL
