TNF

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 similarity

The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.By similarity

GO - Molecular functionⁱ

cytokine activity Source: UniProtKB-KW
identical protein binding Source: Ensembl
protease binding Source: Ensembl
transcription regulatory region sequence-specific DNA binding Source: Ensembl
tumor necrosis factor receptor binding Source: Ensembl

Complete GO annotation on QuickGO ...

GO - Biological processⁱ

activation of cysteine-type endopeptidase activity involved in apoptotic process Source: Ensembl
activation of MAPK activity Source: Ensembl
activation of MAPKKK activity 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 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 chemokine biosynthetic process 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 cytokine secretion 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 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 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 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 pri-miRNA transcription by RNA polymerase II 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 superoxide dismutase activity Source: Ensembl
positive regulation of synaptic transmission Source: Ensembl
positive regulation of synoviocyte proliferation Source: Ensembl
positive regulation of translational initiation by iron Source: Ensembl
positive regulation of vascular associated smooth muscle cell proliferation Source: Ensembl
protein kinase B signaling Source: Ensembl
protein localization to plasma membrane Source: Ensembl
receptor biosynthetic process 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 secretion Source: Ensembl
regulation of insulin secretion 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

Complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	Cytokine

Molecular function

Cytokine

Names & Taxonomyⁱ

Protein namesⁱ	Recommended name: Tumor necrosis factor Alternative name(s): Cachectin TNF-alpha Tumor necrosis factor ligand superfamily member 2 Short name: TNF-a Cleaved into the following 6 chains: Tumor necrosis factor, membrane form Alternative name(s): N-terminal fragment Short name: NTF Intracellular domain 1 Short name: ICD1 Intracellular domain 2 Short name: ICD2 C-domain 1 C-domain 2 Tumor necrosis factor, soluble form
Gene namesⁱ	Name:TNF Synonyms:TNFA, TNFSF2
Organismⁱ	Ovis aries (Sheep)
Taxonomic identifierⁱ	9940 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Laurasiatheria › Artiodactyla › Ruminantia › Pecora › Bovidae › Caprinae › Ovis
Proteomesⁱ	UP000002356 Componentⁱ: Chromosome 20

Subcellular locationⁱ

Topology

Feature key	Position(s)	DescriptionActions	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, Secreted

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	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	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

Sites

Feature key	Position(s)	DescriptionActions	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, Phosphoprotein

Expressionⁱ

Gene expression databases

ExpressionAtlasⁱ	P23383, baseline

ExpressionAtlasⁱ

P23383, baseline

Interactionⁱ

Subunit structureⁱ

Homotrimer.

Interacts with SPPL2B (By similarity).

By similarity

GO - Molecular functionⁱ

cytokine activity Source: UniProtKB-KW
identical protein binding Source: Ensembl
protease binding Source: Ensembl
tumor necrosis factor receptor binding Source: Ensembl

Complete GO annotation on QuickGO ...

Protein-protein interaction databases

STRINGⁱ	9940.ENSOARP00000008936

STRINGⁱ

9940.ENSOARP00000008936

Structureⁱ

3D structure databases

SMRⁱ	P23383
ModBaseⁱ	Search...

Family & Domainsⁱ

Sequence similaritiesⁱ

Belongs to the tumor necrosis factor family.Curated

Keywords - Domainⁱ

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGⁱ	ENOG502S4K8, Eukaryota
Ensembl GeneTree More...GeneTreeⁱ	ENSGT01010000222306
HOGENOMⁱ	CLU_070352_3_1_1
OMAⁱ	GATMLFC
Database of Orthologous Groups More...OrthoDBⁱ	1124938at2759

Family and domain databases

Conserved Domains Database More...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
Pfam protein domain database More...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]FASTA Add to basket

« Hide

        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

Length:234

Mass (Da):25,536

Last modified:February 1, 1994 - v2

Checksum:ⁱ4BCF8CCAB7956B88

GO

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
NCBI Reference Sequences More...RefSeqⁱ	NP_001020031.1, NM_001024860.1 XP_011955827.1, XM_012100437.2

Genome annotation databases

Ensemblⁱ	ENSOART00000009066; ENSOARP00000008936; ENSOARG00000008333 ENSOART00020024817; ENSOARP00020020594; ENSOARG00020016121
GeneIDⁱ	443540
KEGGⁱ	oas:443540

Protein	Similar proteins		Species	Score	Length	Source
P23383	C-domain 1		SHEEP		234	UniRef100_P23383
Tumor necrosis factor alpha (Fragment)		SHEEP		20
TNF-alpha (Fragment)		SHEEP		70

Protein	Similar proteins		Species	Score	Length	Source
P23383	Tumor necrosis factor		BOSTR		234	UniRef90_P23383
Tumor necrosis factor		CAPHI		234
Tumor necrosis factor		BUBBU		233
Tumor necrosis factor (Fragment)		CEREL		229
C-domain 1		SHEEP		234
+15

Protein	Similar proteins		Species	Score	Length	Source
P23383	Tumor necrosis factor		RAT		235	UniRef50_P16599
Tumor necrosis factor		CAVPO		234
Tumor necrosis factor		CAPHI		234
Tumor necrosis factor		BOSTR		234
Tumor necrosis factor		BUBBU		233
+232

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

SMRⁱ	P23383
ModBaseⁱ	Search...

Protein-protein interaction databases

STRINGⁱ	9940.ENSOARP00000008936

STRINGⁱ

9940.ENSOARP00000008936

Genome annotation databases

Ensemblⁱ	ENSOART00000009066; ENSOARP00000008936; ENSOARG00000008333 ENSOART00020024817; ENSOARP00020020594; ENSOARG00020016121
GeneIDⁱ	443540
KEGGⁱ	oas:443540

Organism-specific databases

CTDⁱ	7124

CTDⁱ

7124

Phylogenomic databases

eggNOGⁱ	ENOG502S4K8, Eukaryota
GeneTreeⁱ	ENSGT01010000222306
HOGENOMⁱ	CLU_070352_3_1_1
OMAⁱ	GATMLFC
OrthoDBⁱ	1124938at2759

Gene expression databases

ExpressionAtlasⁱ	P23383, baseline

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
ProtoNetⁱ	Search...
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:	December 2, 2020
	This is version 147 of the entry and version 2 of the sequence. See complete history.
Entry statusⁱ	Reviewed (UniProtKB/Swiss-Prot)
Annotation program	Chordata Protein Annotation Program

UniProtKB

UniParc

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Supporting data

UniProtKB - P23383 (TNFA_SHEEP)

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Tumor necrosis factor

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<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More...</a></p>GO - Molecular functioni

GO - Biological processi

<p>This section provides information about the protein and gene name(s) and synonym(s) and about the organism that is the source of the protein sequence.<p><a href='/help/names_and_taxonomy_section' target='_top'>More...</a></p>Names & Taxonomyi

<p>This section provides information on the location and the topology of the mature protein in the cell.<p><a href='/help/subcellular_location_section' target='_top'>More...</a></p>Subcellular locationi

Plasma membrane

Other locations

Extracellular region or secreted

Extracellular region or secreted

Extracellular region or secreted

Endosome

Extracellular region or secreted

Plasma Membrane

Other locations

Topology

Keywords - Cellular componenti

<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

Molecule processing

Amino acid modifications

Sites

Keywords - PTMi

<p>This section provides information on the expression of a gene at the mRNA or protein level in cells or in tissues of multicellular organisms.<p><a href='/help/expression_section' target='_top'>More...</a></p>Expressioni

Gene expression databases

<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

GO - Molecular functioni

Protein-protein interaction databases

<p>This section provides information on the tertiary and secondary structure of a protein.<p><a href='/help/structure_section' target='_top'>More...</a></p>Structurei

3D structure databases

<p>This section provides information on sequence similarities with other proteins and the domain(s) present in a protein.<p><a href='/help/family_and_domains_section' target='_top'>More...</a></p>Family & Domainsi

<p>This subsection of the 'Family and domains' section provides information about the sequence similarity with other proteins.<p><a href='/help/sequence_similarities' target='_top'>More...</a></p>Sequence similaritiesi

Keywords - Domaini

Phylogenomic databases

Family and domain databases

Experimental Info

Sequence databases

Genome annotation databases

<p>This section is used to point to information related to entries and found in data collections other than UniProtKB.<p><a href='/help/cross_references_section' target='_top'>More...</a></p>Cross-referencesi

Sequence databases

3D structure databases

Protein-protein interaction databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Gene expression databases

Family and domain databases

<p>This section provides general information on the entry.<p><a href='/help/entry_information_section' target='_top'>More...</a></p>Entry informationi

<p>This section contains any relevant information that doesn't fit in any other defined sections<p><a href='/help/miscellaneous_section' target='_top'>More...</a></p>Miscellaneousi

Keywords - Technical termi

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Functionⁱ

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Keywords - Cellular componentⁱ

PTM / Processingⁱ

Keywords - PTMⁱ

Expressionⁱ

Interactionⁱ

GO - Molecular functionⁱ

Structureⁱ

Family & Domainsⁱ

Sequence similaritiesⁱ

Keywords - Domainⁱ

Cross-referencesⁱ

Entry informationⁱ

Miscellaneousⁱ

Keywords - Technical termⁱ