Expression, biological activities and mechanisms of action of A20 (TNFAIP3)

Abstract

A20 (also known as TNFAIP3) is a cytoplasmic protein that plays a key role in the negative regulation of inflammation and immunity. Polymorphisms in the A20 gene locus have been identified as risk alleles for multiple human autoimmune diseases, and A20 has also been proposed to function as a tumor suppressor in several human B-cell lymphomas. A20 expression is strongly induced by multiple stimuli, including the proinflammatory cytokines TNF and IL-1, and microbial products that trigger pathogen recognition receptors, such as Toll-like receptors. A20 functions in a negative feedback loop, which mediates its inhibitory functions by downregulating key proinflammatory signaling pathways, including those controlling NF-κB-and IRF3-dependent gene expression. Activation of these transcription factors is controlled by both K48-and K63-polyubiquitination of upstream signaling proteins, respectively triggering proteasome-mediated degradation or interaction with other signaling proteins. A20 turns off NF-B and IRF3 activation by modulating both types of ubiquitination. Induction of K48-polyubiquitination by A20 involves its C-terminal zincfinger ubiquitin-binding domain, which may promote interaction with E3 ligases, such as Itch and RNF11 that are involved in mediating A20 inhibitory functions. A20 is thought to promote de-ubiquitination of K63-polyubiquitin chains either directly, due to its N-terminal deubiquitinase domain, or by disrupting the interaction between E3 and E2 enzymes that catalyze K63-polyubiquitination. A20 is subject to different mechanisms of regulation, including phosphorylation, proteolytic processing, and association with ubiquitin binding proteins. Here we review the expression and biological activities of A20, as well as the underlying molecular mechanisms.

Inhibiting IκBβ–NFκB signaling attenuates the expression of select pro-inflammatory genes

“…A selection of LPS-induced, MyD88-independent [encoding IP10 (also known as CXCR3), RANTES (also known as CCL5)] and MyD88-dependent (encoding IL1β, CXCL1, TNFα, IL12β, IL6) NFκB-dependent target genes were assessed (Björkbacka et al, 2004). Additionally, target genes that regulate NFκB activity [encoding IκBα, A20 (also known as TNFAIP3)] and antioxidant enzymes (MnSOD) were assessed (Morgan and Liu, 2011;Verstrepen et al, 2010). Three patterns of LPS-induced gene expression were noted with low-dose pharmacological NFκB inhibition.…”

“…(Björkbacka et al, 2004). Additionally, NFκB target genes that regulate NFκB activity (IκBα, A20) and antioxidant enzymes (MnSOD) were assessed (Gilmore and Herscovitch, 2006;Verstrepen et al, 2010). Undoubtedly, LPS-induced expression of other NFκB target genes will also demonstrate variable sensitivity to low-dose parthenolide and BAY 11-7085.…”

C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in β-cells

“…A20 is an ubiquitin-editing enzyme which has both ubiquitin and deubiquitinase activities. 42 Further studies are required to verify whether A20 influences the stability of IkBa, Mcl-1 and/or Bcl-2 proteins. Interestingly, a recent study indicates that IKK may directly phosphorylate and inactivate Bcl-2, 43 suggesting a cross talk between the NF-kB pathway and the Bcl-2 family.…”

Expression of Tumor Necrosis Factor Alpha-Induced Protein 3 mRNA in Peripheral Blood Mononuclear Cells Negatively Correlates with Disease Severity in Psoriasis Vulgaris

“…The N terminus has deubiquitinating activity and can inhibit NF-B signaling by removing K63 polyubiquitination chains from specific NF-B signaling molecules. The Cterminal zinc finger-containing domain possesses E3 ubiquitin ligase activity and can turn off NF-B activation by promoting K48 polyubiquitination of specific NF-B signaling molecules, followed by proteasome-mediated degradation (7,25,27).…”