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UniProtKB - P23383 (TNFA_SHEEP)
Protein
Tumor necrosis factor
Gene
TNF
Organism
Ovis aries (Sheep)
Status
Functioni
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation (By similarity).
Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity).
Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (By similarity).
By similarityThe TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.
By similarityGO - Molecular functioni
- cytokine activity Source: UniProtKB-KW
- identical protein binding Source: Ensembl
- protease binding Source: Ensembl
- transcription cis-regulatory region binding Source: Ensembl
- tumor necrosis factor receptor binding Source: Ensembl
GO - Biological processi
- activation of cysteine-type endopeptidase activity involved in apoptotic process Source: Ensembl
- cellular response to amino acid stimulus Source: Ensembl
- cellular response to nicotine Source: Ensembl
- cellular response to organic cyclic compound Source: Ensembl
- chronic inflammatory response to antigenic stimulus Source: Ensembl
- cortical actin cytoskeleton organization Source: Ensembl
- defense response to Gram-positive bacterium Source: Ensembl
- embryonic digestive tract development Source: Ensembl
- endothelial cell apoptotic process Source: Ensembl
- epithelial cell proliferation involved in salivary gland morphogenesis Source: Ensembl
- extracellular matrix organization Source: Ensembl
- extrinsic apoptotic signaling pathway via death domain receptors Source: Ensembl
- glucose metabolic process Source: Ensembl
- humoral immune response Source: Ensembl
- intrinsic apoptotic signaling pathway in response to DNA damage Source: Ensembl
- JNK cascade Source: Ensembl
- leukocyte tethering or rolling Source: Ensembl
- lipopolysaccharide-mediated signaling pathway Source: Ensembl
- microglial cell activation Source: Ensembl
- necroptotic signaling pathway Source: UniProtKB
- negative regulation of alkaline phosphatase activity Source: Ensembl
- negative regulation of amyloid-beta clearance Source: Ensembl
- negative regulation of bicellular tight junction assembly Source: Ensembl
- negative regulation of blood vessel endothelial cell migration Source: Ensembl
- negative regulation of branching involved in lung morphogenesis Source: Ensembl
- negative regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: Ensembl
- negative regulation of cytokine production involved in immune response Source: Ensembl
- negative regulation of endothelial cell proliferation Source: Ensembl
- negative regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: Ensembl
- negative regulation of glucose import Source: Ensembl
- negative regulation of interleukin-6 production Source: Ensembl
- negative regulation of lipid catabolic process Source: Ensembl
- negative regulation of mitotic cell cycle Source: Ensembl
- negative regulation of myoblast differentiation Source: Ensembl
- negative regulation of myosin-light-chain-phosphatase activity Source: Ensembl
- negative regulation of osteoblast differentiation Source: Ensembl
- negative regulation of production of miRNAs involved in gene silencing by miRNA Source: Ensembl
- negative regulation of protein-containing complex disassembly Source: Ensembl
- negative regulation of signaling receptor activity Source: Ensembl
- negative regulation of transcription by RNA polymerase II Source: Ensembl
- negative regulation of vascular wound healing Source: Ensembl
- negative regulation of viral genome replication Source: Ensembl
- osteoclast differentiation Source: Ensembl
- positive regulation of amyloid-beta formation Source: Ensembl
- positive regulation of blood microparticle formation Source: Ensembl
- positive regulation of calcidiol 1-monooxygenase activity Source: Ensembl
- positive regulation of calcineurin-NFAT signaling cascade Source: Ensembl
- positive regulation of chemokine (C-X-C motif) ligand 2 production Source: Ensembl
- positive regulation of chronic inflammatory response to antigenic stimulus Source: Ensembl
- positive regulation of cytokine production involved in inflammatory response Source: Ensembl
- positive regulation of fever generation Source: Ensembl
- positive regulation of glial cell proliferation Source: Ensembl
- positive regulation of hair follicle development Source: Ensembl
- positive regulation of heterotypic cell-cell adhesion Source: Ensembl
- positive regulation of humoral immune response mediated by circulating immunoglobulin Source: Ensembl
- positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
- positive regulation of I-kappaB phosphorylation Source: Ensembl
- positive regulation of interferon-gamma production Source: Ensembl
- positive regulation of interleukin-1 beta production Source: Ensembl
- positive regulation of interleukin-33 production Source: Ensembl
- positive regulation of interleukin-6 production Source: Ensembl
- positive regulation of interleukin-8 production Source: Ensembl
- positive regulation of JNK cascade Source: Ensembl
- positive regulation of JUN kinase activity Source: Ensembl
- positive regulation of leukocyte adhesion to arterial endothelial cell Source: Ensembl
- positive regulation of membrane protein ectodomain proteolysis Source: Ensembl
- positive regulation of miRNA transcription Source: Ensembl
- positive regulation of neuron apoptotic process Source: Ensembl
- positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
- positive regulation of NIK/NF-kappaB signaling Source: Ensembl
- positive regulation of nitric oxide biosynthetic process Source: Ensembl
- positive regulation of osteoclast differentiation Source: Ensembl
- positive regulation of peptidyl-serine phosphorylation Source: Ensembl
- positive regulation of phagocytosis Source: Ensembl
- positive regulation of podosome assembly Source: Ensembl
- positive regulation of protein-containing complex disassembly Source: Ensembl
- positive regulation of protein kinase B signaling Source: Ensembl
- positive regulation of protein localization to cell surface Source: Ensembl
- positive regulation of protein localization to plasma membrane Source: Ensembl
- positive regulation of protein transport Source: Ensembl
- positive regulation of superoxide dismutase activity Source: Ensembl
- positive regulation of synaptic transmission Source: Ensembl
- positive regulation of synoviocyte proliferation Source: Ensembl
- positive regulation of transcription by RNA polymerase II Source: Ensembl
- positive regulation of translational initiation by iron Source: Ensembl
- positive regulation of vascular associated smooth muscle cell proliferation Source: Ensembl
- positive regulation of vitamin D biosynthetic process Source: Ensembl
- protein kinase B signaling Source: Ensembl
- protein localization to plasma membrane Source: Ensembl
- regulation of branching involved in salivary gland morphogenesis Source: Ensembl
- regulation of endothelial cell apoptotic process Source: Ensembl
- regulation of establishment of endothelial barrier Source: Ensembl
- regulation of immunoglobulin production Source: Ensembl
- regulation of insulin secretion Source: Ensembl
- regulation of reactive oxygen species metabolic process Source: Ensembl
- regulation of synapse organization Source: Ensembl
- response to glucocorticoid Source: Ensembl
- response to virus Source: Ensembl
- sequestering of triglyceride Source: Ensembl
- tumor necrosis factor-mediated signaling pathway Source: Ensembl
- vascular endothelial growth factor production Source: UniProtKB
Keywordsi
| Molecular function | Cytokine |
Names & Taxonomyi
| Protein namesi | Recommended name: Tumor necrosis factorAlternative name(s): Cachectin TNF-alpha Tumor necrosis factor ligand superfamily member 2 Short name: TNF-a Cleaved into the following 6 chains: Alternative name(s): N-terminal fragment Short name: NTF |
| Gene namesi | Name:TNF Synonyms:TNFA, TNFSF2 |
| Organismi | Ovis aries (Sheep) |
| Taxonomic identifieri | 9940 [NCBI] |
| Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Laurasiatheria › Artiodactyla › Ruminantia › Pecora › Bovidae › Caprinae › Ovis |
| Proteomesi |
|
Subcellular locationi
Plasma membrane
- Cell membrane By similarity; Single-pass type II membrane protein By similarity
Other locations
- Membrane By similarity; Single-pass type II membrane protein By similarity
Extracellular region or secreted
- Secreted By similarity
Extracellular region or secreted
- Secreted By similarity
Extracellular region or secreted
- Secreted By similarity
Endosome
- recycling endosome Source: Ensembl
Extracellular region or secreted
- extracellular space Source: UniProtKB-KW
Plasma Membrane
- external side of plasma membrane Source: Ensembl
- integral component of plasma membrane Source: Ensembl
- phagocytic cup Source: Ensembl
Other locations
- membrane raft Source: Ensembl
Topology
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Topological domaini | 1 – 35 | CytoplasmicSequence analysisAdd BLAST | 35 | |
| Transmembranei | 36 – 56 | Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST | 21 | |
| Topological domaini | 57 – 234 | ExtracellularSequence analysisAdd BLAST | 178 |
Keywords - Cellular componenti
Cell membrane, Membrane, SecretedPTM / Processingi
Molecule processing
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| ChainiPRO_0000034455 | 1 – 234 | Tumor necrosis factor, membrane formAdd BLAST | 234 | |
| ChainiPRO_0000417295 | 1 – 39 | Intracellular domain 1By similarityAdd BLAST | 39 | |
| ChainiPRO_0000417296 | 1 – 35 | Intracellular domain 2By similarityAdd BLAST | 35 | |
| ChainiPRO_0000417297 | 50 – ? | C-domain 1By similarity | ||
| ChainiPRO_0000417298 | 52 – ? | C-domain 2By similarity | ||
| ChainiPRO_0000034456 | 78 – 234 | Tumor necrosis factor, soluble formAdd BLAST | 157 |
Amino acid modifications
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Modified residuei | 2 | Phosphoserine; by CK1By similarity | 1 | |
| Lipidationi | 20 | N6-myristoyl lysineBy similarity | 1 | |
| Glycosylationi | 81 | O-linked (GalNAc...) serine; in soluble formBy similarity | 1 | |
| Glycosylationi | 96 | N-linked (GlcNAc...) asparagineSequence analysis | 1 | |
| Disulfide bondi | 146 ↔ 178 | By similarity |
Post-translational modificationi
The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space (By similarity).By similarity
The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1 (By similarity).By similarity
O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.By similarity
The soluble form is demyristoylated by SIRT6, promoting its secretion.By similarity
Sites
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Sitei | 34 – 35 | Cleavage; by SPPL2A or SPPL2BBy similarity | 2 | |
| Sitei | 39 – 40 | Cleavage; by SPPL2A or SPPL2BBy similarity | 2 | |
| Sitei | 49 – 50 | Cleavage; by SPPL2A or SPPL2BBy similarity | 2 | |
| Sitei | 51 – 52 | Cleavage; by SPPL2A or SPPL2BBy similarity | 2 | |
| Sitei | 77 – 78 | Cleavage; by ADAM17By similarity | 2 |
Keywords - PTMi
Disulfide bond, Glycoprotein, Lipoprotein, Myristate, PhosphoproteinInteractioni
Subunit structurei
Homotrimer.
Interacts with SPPL2B (By similarity).
By similarityGO - Molecular functioni
- cytokine activity Source: UniProtKB-KW
- identical protein binding Source: Ensembl
- protease binding Source: Ensembl
- tumor necrosis factor receptor binding Source: Ensembl
Protein-protein interaction databases
| STRINGi | 9940.ENSOARP00000008936 |
Family & Domainsi
Sequence similaritiesi
Belongs to the tumor necrosis factor family.Curated
Keywords - Domaini
Signal-anchor, Transmembrane, Transmembrane helixPhylogenomic databases
| eggNOGi | ENOG502S4K8, Eukaryota |
| HOGENOMi | CLU_070352_3_1_1 |
| OMAi | GATMLFC |
| OrthoDBi | 1124938at2759 |
Family and domain databases
| CDDi | cd00184, TNF, 1 hit |
| Gene3Di | 2.60.120.40, 1 hit |
| InterProi | View protein in InterPro IPR006053, TNF IPR002959, TNF_alpha IPR021184, TNF_CS IPR006052, TNF_dom IPR008983, Tumour_necrosis_fac-like_dom |
| PANTHERi | PTHR11471:SF23, PTHR11471:SF23, 1 hit |
| Pfami | View protein in Pfam PF00229, TNF, 1 hit |
| PRINTSi | PR01234, TNECROSISFCT PR01235, TNFALPHA |
| SMARTi | View protein in SMART SM00207, TNF, 1 hit |
| SUPFAMi | SSF49842, SSF49842, 1 hit |
| PROSITEi | View protein in PROSITE PS00251, TNF_1, 1 hit PS50049, TNF_2, 1 hit |
Sequencei
Sequence statusi: Complete.
Sequence processingi: The displayed sequence is further processed into a mature form.
P23383-1 [UniParc]FASTAAdd to basket
10 20 30 40 50
MSTKSMIRDV ELAEEVLSNK AGGPQGSRSC WCLSLFSFLL VAGATTLFCL
60 70 80 90 100
LHFGVIGPQR EEQSPAGPSF NRPLVQTLRS SSQASNNKPV AHVVANISAP
110 120 130 140 150
GQLRWGDSYA NALMANGVEL KDNQLVVPTD GLYLIYSQVL FRGHGCPSTP
160 170 180 190 200
LFLTHTISRI AVSYQTKVNI LSAIKSPCHR ETLEGAEAKP WYEPIYQGGV
210 220 230
FQLEKGDRLS AEINLPEYLD YAESGQVYFG IIAL
Experimental Info
| Feature key | Position(s) | DescriptionActions | Graphical view | Length |
|---|---|---|---|---|
| Sequence conflicti | 63 | Missing in CAA39437 (PubMed:2251151).Curated | 1 |
Sequence databases
| Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X55966 mRNA Translation: CAA39437.1 X55152 mRNA Translation: CAA38952.1 X56756 mRNA Translation: CAA40076.1 |
| PIRi | JH0529 |
| RefSeqi | NP_001020031.1, NM_001024860.1 XP_011955827.1, XM_012100437.2 |
Genome annotation databases
| Ensembli | ENSOART00000009066; ENSOARP00000008936; ENSOARG00000008333 |
| GeneIDi | 443540 |
| KEGGi | oas:443540 |
Similar proteinsi
Cross-referencesi
Sequence databases
| Select the link destinations: EMBLi GenBanki DDBJi Links Updated | X55966 mRNA Translation: CAA39437.1 X55152 mRNA Translation: CAA38952.1 X56756 mRNA Translation: CAA40076.1 |
| PIRi | JH0529 |
| RefSeqi | NP_001020031.1, NM_001024860.1 XP_011955827.1, XM_012100437.2 |
3D structure databases
| AlphaFoldDBi | P23383 |
| SMRi | P23383 |
| ModBasei | Search... |
Protein-protein interaction databases
| STRINGi | 9940.ENSOARP00000008936 |
Genome annotation databases
| Ensembli | ENSOART00000009066; ENSOARP00000008936; ENSOARG00000008333 |
| GeneIDi | 443540 |
| KEGGi | oas:443540 |
Organism-specific databases
| CTDi | 7124 |
Phylogenomic databases
| eggNOGi | ENOG502S4K8, Eukaryota |
| HOGENOMi | CLU_070352_3_1_1 |
| OMAi | GATMLFC |
| OrthoDBi | 1124938at2759 |
Gene expression databases
| ExpressionAtlasi | P23383, baseline |
Family and domain databases
| CDDi | cd00184, TNF, 1 hit |
| Gene3Di | 2.60.120.40, 1 hit |
| InterProi | View protein in InterPro IPR006053, TNF IPR002959, TNF_alpha IPR021184, TNF_CS IPR006052, TNF_dom IPR008983, Tumour_necrosis_fac-like_dom |
| PANTHERi | PTHR11471:SF23, PTHR11471:SF23, 1 hit |
| Pfami | View protein in Pfam PF00229, TNF, 1 hit |
| PRINTSi | PR01234, TNECROSISFCT PR01235, TNFALPHA |
| SMARTi | View protein in SMART SM00207, TNF, 1 hit |
| SUPFAMi | SSF49842, SSF49842, 1 hit |
| PROSITEi | View protein in PROSITE PS00251, TNF_1, 1 hit PS50049, TNF_2, 1 hit |
| MobiDBi | Search... |
Entry informationi
| Entry namei | TNFA_SHEEP | |
| Accessioni | P23383Primary (citable) accession number: P23383 | |
| Entry historyi | Integrated into UniProtKB/Swiss-Prot: | November 1, 1991 |
| Last sequence update: | February 1, 1994 | |
| Last modified: | May 25, 2022 | |
| This is version 152 of the entry and version 2 of the sequence. See complete history. | ||
| Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
| Annotation program | Chordata Protein Annotation Program | |
Miscellaneousi
Keywords - Technical termi
Reference proteomeDocuments
- SIMILARITY comments
Index of protein domains and families
