TNFA_DELLE
ID TNFA_DELLE Reviewed; 233 AA.
AC Q8WNR1;
DT 06-JUN-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2002, sequence version 1.
DT 03-AUG-2022, entry version 105.
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 Delphinapterus leucas (Beluga whale).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Whippomorpha; Cetacea; Odontoceti;
OC Monodontidae; Delphinapterus.
OX NCBI_TaxID=9749;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11768130;
RA Denis F., Archambault D.;
RT "Molecular cloning and characterization of beluga whale (Delphinapterus
RT leucas) interleukin-1beta and tumor necrosis factor-alpha.";
RL Can. J. Vet. Res. 65:233-240(2001).
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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF320323; AAL56946.1; -; mRNA.
DR AlphaFoldDB; Q8WNR1; -.
DR SMR; Q8WNR1; -.
DR STRING; 9749.Q8WNR1; -.
DR Ensembl; ENSDLET00000029714; ENSDLEP00000027030; ENSDLEG00000019530.
DR OrthoDB; 1124938at2759; -.
DR Proteomes; UP000248483; Unplaced.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IEA:UniProtKB-KW.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:Ensembl.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0001891; C:phagocytic cup; IEA:Ensembl.
DR GO; GO:0055037; C:recycling endosome; IEA:Ensembl.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0002020; F:protease binding; IEA:Ensembl.
DR GO; GO:0000976; F:transcription cis-regulatory region binding; IEA:Ensembl.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:Ensembl.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0071316; P:cellular response to nicotine; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IEA:Ensembl.
DR GO; GO:0002439; P:chronic inflammatory response to antigenic stimulus; IEA:Ensembl.
DR GO; GO:0030866; P:cortical actin cytoskeleton organization; IEA:Ensembl.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl.
DR GO; GO:0048566; P:embryonic digestive tract development; IEA:Ensembl.
DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IEA:Ensembl.
DR GO; GO:0030198; P:extracellular matrix organization; IEA:Ensembl.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl.
DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl.
DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IEA:Ensembl.
DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl.
DR GO; GO:0050901; P:leukocyte tethering or rolling; IEA:Ensembl.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl.
DR GO; GO:0097527; P:necroptotic signaling pathway; ISS:CAFA.
DR GO; GO:0010693; P:negative regulation of alkaline phosphatase activity; IEA:Ensembl.
DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; IEA:Ensembl.
DR GO; GO:1903347; P:negative regulation of bicellular tight junction assembly; IEA:Ensembl.
DR GO; GO:0043537; P:negative regulation of blood vessel endothelial cell migration; IEA:Ensembl.
DR GO; GO:0061048; P:negative regulation of branching involved in lung morphogenesis; IEA:Ensembl.
DR GO; GO:0043154; P:negative regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0002719; P:negative regulation of cytokine production involved in immune response; IEA:Ensembl.
DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IEA:Ensembl.
DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IEA:Ensembl.
DR GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IEA:Ensembl.
DR GO; GO:1903799; P:negative regulation of miRNA maturation; IEA:Ensembl.
DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IEA:Ensembl.
DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IEA:Ensembl.
DR GO; GO:0035509; P:negative regulation of myosin-light-chain-phosphatase activity; IEA:Ensembl.
DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl.
DR GO; GO:0043242; P:negative regulation of protein-containing complex disassembly; ISS:UniProtKB.
DR GO; GO:2000272; P:negative regulation of signaling receptor activity; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0061044; P:negative regulation of vascular wound healing; IEA:Ensembl.
DR GO; GO:0045071; P:negative regulation of viral genome replication; IEA:Ensembl.
DR GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; ISS:UniProtKB.
DR GO; GO:2000334; P:positive regulation of blood microparticle formation; IEA:Ensembl.
DR GO; GO:0060559; P:positive regulation of calcidiol 1-monooxygenase activity; IEA:Ensembl.
DR GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IEA:Ensembl.
DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IEA:Ensembl.
DR GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl.
DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IEA:Ensembl.
DR GO; GO:0031622; P:positive regulation of fever generation; IEA:Ensembl.
DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IEA:Ensembl.
DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl.
DR GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; IEA:Ensembl.
DR GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:1903721; P:positive regulation of I-kappaB phosphorylation; IEA:Ensembl.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl.
DR GO; GO:0032731; P:positive regulation of interleukin-1 beta production; IEA:Ensembl.
DR GO; GO:0150129; P:positive regulation of interleukin-33 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IEA:Ensembl.
DR GO; GO:0046330; P:positive regulation of JNK cascade; IEA:Ensembl.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; ISS:UniProtKB.
DR GO; GO:1904999; P:positive regulation of leukocyte adhesion to arterial endothelial cell; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; ISS:UniProtKB.
DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IEA:Ensembl.
DR GO; GO:1902895; P:positive regulation of miRNA transcription; IEA:Ensembl.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IEA:Ensembl.
DR GO; GO:0050766; P:positive regulation of phagocytosis; IEA:Ensembl.
DR GO; GO:0071803; P:positive regulation of podosome assembly; IEA:Ensembl.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IEA:Ensembl.
DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IEA:Ensembl.
DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; ISS:UniProtKB.
DR GO; GO:0051222; P:positive regulation of protein transport; IEA:Ensembl.
DR GO; GO:0043243; P:positive regulation of protein-containing complex disassembly; ISS:UniProtKB.
DR GO; GO:1901671; P:positive regulation of superoxide dismutase activity; IEA:Ensembl.
DR GO; GO:0050806; P:positive regulation of synaptic transmission; IEA:Ensembl.
DR GO; GO:1901647; P:positive regulation of synoviocyte proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0045994; P:positive regulation of translational initiation by iron; IEA:Ensembl.
DR GO; GO:1904707; P:positive regulation of vascular associated smooth muscle cell proliferation; IEA:Ensembl.
DR GO; GO:0060557; P:positive regulation of vitamin D biosynthetic process; IEA:Ensembl.
DR GO; GO:0043491; P:protein kinase B signaling; IEA:Ensembl.
DR GO; GO:0072659; P:protein localization to plasma membrane; IEA:Ensembl.
DR GO; GO:0060693; P:regulation of branching involved in salivary gland morphogenesis; IEA:Ensembl.
DR GO; GO:2000351; P:regulation of endothelial cell apoptotic process; IEA:Ensembl.
DR GO; GO:1903140; P:regulation of establishment of endothelial barrier; IEA:Ensembl.
DR GO; GO:0002637; P:regulation of immunoglobulin production; IEA:Ensembl.
DR GO; GO:0050796; P:regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:2000377; P:regulation of reactive oxygen species metabolic process; IEA:Ensembl.
DR GO; GO:0050807; P:regulation of synapse organization; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid; IEA:Ensembl.
DR GO; GO:0009615; P:response to virus; IEA:Ensembl.
DR GO; GO:0030730; P:sequestering of triglyceride; IEA:Ensembl.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IEA:Ensembl.
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; Phosphoprotein; Reference proteome; Secreted;
KW Signal-anchor; Transmembrane; Transmembrane helix.
FT CHAIN 1..233
FT /note="Tumor necrosis factor, membrane form"
FT /id="PRO_0000034417"
FT CHAIN 1..39
FT /note="Intracellular domain 1"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417219"
FT CHAIN 1..35
FT /note="Intracellular domain 2"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417220"
FT CHAIN 50..?
FT /note="C-domain 1"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417221"
FT CHAIN 52..?
FT /note="C-domain 2"
FT /evidence="ECO:0000250"
FT /id="PRO_0000417222"
FT CHAIN 78..233
FT /note="Tumor necrosis factor, soluble form"
FT /id="PRO_0000034418"
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..233
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT SITE 34..35
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 19
FT /note="N6-myristoyl lysine"
FT /evidence="ECO:0000250|UniProtKB:P01375"
FT CARBOHYD 80
FT /note="O-linked (GalNAc...) serine; in soluble form"
FT /evidence="ECO:0000250"
FT CARBOHYD 95
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 145..177
FT /evidence="ECO:0000250"
SQ SEQUENCE 233 AA; 25420 MW; 2DF37DCB2BC9E961 CRC64;
MSTESMIRDV ELAEEALSKT AGGSQGSGRC LCLSLFSFFL VAGGTTLFCL LHFGVIGPQR
EEFPTGYSII SPLAQTLRSS SKTSSNKPVA HVVANLSAQG QLRWLNTYAN TLLANSVKLE
DNQLVVPTDG LYLIYSQVLF RGQGCPSTHL FLTHTISRIA VSYQTKVNLL SAIKSPCQRE
TPEGAEAKPW YEPIYQGGVF QLEKGDRLSA EINLPDYLDF AESGQVYFGI IAL
