UniProt functional annotation for P01375



	UniProt functional annotation for P01375

UniProt code: P01375.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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. Impairs regulatory T- cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918, PubMed:16829952, PubMed:23396208). 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 (PubMed:12794819). {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}.

Function: The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. {ECO:0000269|PubMed:16829952}.

Subunit: Homotrimer. Interacts with SPPL2B. {ECO:0000269|PubMed:16829951}.

Subcellular location: Cell membrane {ECO:0000269|PubMed:16829952}; Single-pass type II membrane protein {ECO:0000269|PubMed:16829952}.

Subcellular location: [Tumor necrosis factor, membrane form]: Membrane; Single-pass type II membrane protein.

Subcellular location: [Tumor necrosis factor, soluble form]: Secreted.

Subcellular location: [C-domain 1]: Secreted.

Subcellular location: [C-domain 2]: Secreted.

Ptm: 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. {ECO:0000269|PubMed:16829951, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:9034191}.

Ptm: 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. {ECO:0000269|PubMed:10205166, ECO:0000269|PubMed:8597870}.

Ptm: O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. {ECO:0000269|PubMed:8631363}.

Polymorphism: Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].

Polymorphism: Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].

Disease: Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity: Belongs to the tumor necrosis factor family. {ECO:0000305}.

Sequence caution: Sequence=AAF71992.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=CAA75070.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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. Impairs regulatory T- cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918, PubMed:16829952, PubMed:23396208). 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 (PubMed:12794819). {ECO:0000250\|UniProtKB:P06804, ECO:0000269\|PubMed:12794819, ECO:0000269\|PubMed:16829952, ECO:0000269\|PubMed:22517918, ECO:0000269\|PubMed:23396208}.



Function:		The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. {ECO:0000269\|PubMed:16829952}.


Subunit:		Homotrimer. Interacts with SPPL2B. {ECO:0000269\|PubMed:16829951}.
Subcellular location:		Cell membrane {ECO:0000269\|PubMed:16829952}; Single-pass type II membrane protein {ECO:0000269\|PubMed:16829952}.
Subcellular location:		[Tumor necrosis factor, membrane form]: Membrane; Single-pass type II membrane protein.
Subcellular location:		[Tumor necrosis factor, soluble form]: Secreted.
Subcellular location:		[C-domain 1]: Secreted.
Subcellular location:		[C-domain 2]: Secreted.
Ptm:		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. {ECO:0000269\|PubMed:16829951, ECO:0000269\|PubMed:16829952, ECO:0000269\|PubMed:9034191}.
Ptm:		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. {ECO:0000269\|PubMed:10205166, ECO:0000269\|PubMed:8597870}.
Ptm:		O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. {ECO:0000269\|PubMed:8631363}.
Polymorphism:		Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424].
Polymorphism:		Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].
Disease:		Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis). {ECO:0000269\|PubMed:12746914}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Similarity:		Belongs to the tumor necrosis factor family. {ECO:0000305}.
Sequence caution:		Sequence=AAF71992.1; Type=Frameshift; Evidence={ECO:0000305}; Sequence=CAA75070.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};