Tumor necrosis factor, alpha-induced protein 3 or A20 is a protein that in humans is encoded by the TNFAIP3 gene. [5] [6]
This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein and a deubiquitinating enzyme, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. The A20 protein is ancient, and protein homolog can be found as far back as cnidaria (corals, jellyfish, anemones) with a conserved protein domain composition. [7] Using knockout mouse models of TNFAIP3 and its transcriptional repressor (i.e. KCHIP3), TNFAIP3 has been shown to be critical for limiting inflammation by terminating endotoxin- and TNF-induced NF-kappa B responses. [8] [9] [10] In brief, deubiquitinase function of TNFAIP3 was shown to remove ubiquitin chains from VE-cadherin to prevent loss of VE-cadherin at the endothelial adherens junctions. [9]
TNFAIP3 has been shown to interact with TNIP1, [11] TRAF1, [12] [13] TRAF2, [12] IKBKG, [14] TAX1BP1, [15] YWHAB, [16] YWHAZ, [16] [17] TRAF6 [13] [18] and YWHAH. [16] [17]
The TNFAIP3 locus is implicated as a positively associated factor in rheumatoid arthritis (RA). The rs5029937 (T) and the rs6920220 (A) SNPs increase risk of RA by 20 to 40% respectively. [19] A third SNP, rs10499194 (T) is found less often in rheumatoid arthritis but this negative association may not be statistically meaningful.
An association with infantile onset intractable inflammatory bowel disease has also been reported. [20]
Receptor activator of nuclear factor κ B (RANK), also known as TRANCE receptor or TNFRSF11A, is a member of the tumor necrosis factor receptor (TNFR) molecular sub-family. RANK is the receptor for RANK-Ligand (RANKL) and part of the RANK/RANKL/OPG signaling pathway that regulates osteoclast differentiation and activation. It is associated with bone remodeling and repair, immune cell function, lymph node development, thermal regulation, and mammary gland development. Osteoprotegerin (OPG) is a decoy receptor for RANKL, and regulates the stimulation of the RANK signaling pathway by competing for RANKL. The cytoplasmic domain of RANK binds TRAFs 1, 2, 3, 5, and 6 which transmit signals to downstream targets such as NF-κB and JNK.
TRAF6 is a TRAF human protein.
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.
Tumor necrosis factor receptor type 1-associated DEATH domain protein is a protein that in humans is encoded by the TRADD gene.
IKK-β also known as inhibitor of nuclear factor kappa-B kinase subunit beta is a protein that in humans is encoded by the IKBKB gene.
Tumor necrosis factor receptor 1 (TNFR1), also known as tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) and CD120a, is a ubiquitous membrane receptor that binds tumor necrosis factor-alpha (TNFα).
Inhibitor of nuclear factor kappa-B kinase subunit alpha (IKK-α) also known as IKK1 or conserved helix-loop-helix ubiquitous kinase (CHUK) is a protein kinase that in humans is encoded by the CHUK gene. IKK-α is part of the IκB kinase complex that plays an important role in regulating the NF-κB transcription factor. However, IKK-α has many additional cellular targets, and is thought to function independently of the NF-κB pathway to regulate epidermal differentiation.
Baculoviral IAP repeat-containing protein 2 is a protein that in humans is encoded by the BIRC2 gene.
TNF receptor-associated factor 1 is a protein that in humans is encoded by the TRAF1 gene.
TNF receptor-associated factor 5 is a protein that in humans is encoded by the TRAF5 gene.
TNF receptor-associated factor (TRAF3) is a protein that in humans is encoded by the TRAF3 gene.
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions in a variety of cellular pathways related to both cell survival and death. In terms of cell death, RIPK1 plays a role in apoptosis and necroptosis. Some of the cell survival pathways RIPK1 participates in include NF-κB, Akt, and JNK.
Mitogen-activated protein kinase kinase kinase 14 also known as NF-kappa-B-inducing kinase (NIK) is an enzyme that in humans is encoded by the MAP3K14 gene.
TNFAIP3-interacting protein 1, also known as ABIN-1, is a protein that in humans is encoded by the TNIP1 gene.
TNF receptor-associated factor 4 (TRAF4) also known as RING finger protein 83 (RNF83) is a protein that in humans is encoded by the TRAF4 gene.
TRAF family member-associated NF-kappa-B activator is a protein that in humans is encoded by the TANK gene.
Tax1-binding protein 1 is a protein that in humans is encoded by the TAX1BP1 gene.
TNFAIP3-interacting protein 2 is a protein that in humans is encoded by the TNIP2 gene. TNIP2 contains multiple amino acid sites that are phosphorylated and ubiquitinated.
Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) and CD120b, is one of two membrane receptors that binds tumor necrosis factor-alpha (TNFα). Like its counterpart, tumor necrosis factor receptor 1 (TNFR1), the extracellular region of TNFR2 consists of four cysteine-rich domains which allow for binding to TNFα. TNFR1 and TNFR2 possess different functions when bound to TNFα due to differences in their intracellular structures, such as TNFR2 lacking a death domain (DD).
TNFAIP3 interacting protein 3 is a protein that in humans is encoded by the TNIP3 gene.