Tumor necrosis factor, alpha-induced protein 3 or A20 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''TNFAIP3''
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
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
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
and a
deubiquitinating enzyme
Deubiquitinating enzymes (DUBs), also known as deubiquitinating peptidases, deubiquitinating isopeptidases, deubiquitinases, ubiquitin proteases, ubiquitin hydrolases, ubiquitin isopeptidases, are a large group of proteases that cleave ubiquitin f ...
, and has been shown to inhibit
NF-kappa B activation as well as TNF-mediated
apoptosis. The A20 protein is ancient, and protein
homolog
In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...
can be found as far back as
cnidaria
Cnidaria () is a phylum under kingdom Animalia containing over 11,000 species of aquatic animals found both in freshwater and marine environments, predominantly the latter.
Their distinguishing feature is cnidocytes, specialized cells that ...
(corals, jellyfish, anemones) with a conserved
protein domain
In molecular biology, a protein domain is a region of a protein's polypeptide chain that is self-stabilizing and that folds independently from the rest. Each domain forms a compact folded three-dimensional structure. Many proteins consist of ...
composition.
Using knockout mouse models of TNFAIP3 and its transcriptional repressor (i.e.
KCHIP3
Calsenilin is a protein that in humans is encoded by the ''KCNIP3'' gene.
Function
This gene encodes a member of the family of voltage-gated potassium (Kv) channel-interacting proteins, which belong to the neuronal calcium sensor family of pro ...
), TNFAIP3 has been shown to be critical for limiting inflammation by terminating endotoxin- and TNF-induced NF-kappa B responses.
In brief, deubiquitinase function of TNFAIP3 was shown to remove ubiquitin chains from
VE-cadherin
Cadherin 5, type 2 or VE-cadherin (vascular endothelial cadherin) also known as CD144 ( Cluster of Differentiation 144), is a type of cadherin. It is encoded by the human gene ''CDH5''.
Function
VE-cadherin is a classical cadherin from the cad ...
to prevent loss of VE-cadherin at the endothelial
adherens junction
Adherens junctions (or zonula adherens, intermediate junction, or "belt desmosome") are protein complexes that occur at cell–cell junctions, cell–matrix junctions in epithelial and endothelial tissues, usually more basal than tight junctions. ...
s.
Interactions
TNFAIP3 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with
TNIP1
TNFAIP3-interacting protein 1, also known as ABIN-1, is a protein that in humans is encoded by the ''TNIP1'' gene.
Association with autoimmune diseases
Genetic variations within the region of the ''TNIP1'' gene have been shown to have associ ...
,
TRAF1
TNF receptor-associated factor 1 is a protein that in humans is encoded by the ''TRAF1'' gene.
Function
The protein encoded by this gene is a member of the TNF receptor (TNFR) associated factor (TRAF) protein family. TRAF proteins associate wit ...
,
TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the ''TRAF2'' gene.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, an ...
,
[ ]IKBKG
NF-kappa-B essential modulator (NEMO) also known as inhibitor of nuclear factor kappa-B kinase subunit gamma (IKK-γ) is a protein that in humans is encoded by the ''IKBKG'' gene. NEMO is a subunit of the IκB kinase complex that activates NF-κ ...
,TAX1BP1
Tax1-binding protein 1 is a protein that in humans is encoded by the ''TAX1BP1'' gene.
Interactions
TAX1BP1 has been shown to interact with TNFAIP3 and TRAF6. TAX1BP1 binds to TNFAIP3
Tumor necrosis factor, alpha-induced protein 3 or A20 i ...
,YWHAB
14-3-3 protein beta/alpha is a protein that in humans is encoded by the ''YWHAB'' gene.
Function
This gene encodes a protein belonging to the 14-3-3 family of proteins, members of which mediate signal transduction by binding to phosphoserine-c ...
,YWHAZ
14-3-3 protein zeta/delta (14-3-3ζ) is a protein that in humans is encoded by the ''YWHAZ'' gene on chromosome 8. The protein encoded by this gene is a member of the 14-3-3 protein family and a central hub protein for many signal transduction pat ...
,TRAF6
TRAF6 is a TRAF human protein.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF recep ...
YWHAH
14-3-3 protein eta also referred to as 14-3-3η is a protein that in humans is encoded by the ''YWHAH'' gene.
Function
This gene product belongs to the 14-3-3 family of proteins that are normally intracellular in nature and help to mediate si ...
.[
]
Association with rheumatoid arthritis
The TNFAIP3 locus is implicated as a positively associated factor in rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...
(RA). The rs5029937 (T) and the rs6920220 (A) SNPs
In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently larg ...
increase risk of RA by 20 to 40% respectively.
Other diseases
An association with infantile onset intractable inflammatory bowel disease has also been reported.[Zheng C, Huang Y, Ye Z, Wang Y, Tang Z, Lu J, Wu J, Zhou Y, Wang L, Huang Z, Yang H, Xue A (2018) Infantile onset intractable inflammatory bowel disease due to novel heterozygous mutations in TNFAIP3 (A20). Inflamm Bowel Dis doi: 10.1093/ibd/izy165 ]
See also
* Haploinsufficiency of A20
Haploinsufficiency of A20 is a rare disease caused by mutations in the gene ''TNFAIP3''.Demir S, Sonmez HE, OZen S (2018) Vasculitis: Decade in Review. Curr Rheumatol Rev doi: 10.2174/1573397114666180726093731Aeschlimann FA, Batu ED, Canna SW, Go ...
References
Further reading
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External links
* {{PDBe-KB2, P21580, Tumor necrosis factor alpha-induced protein 3