A20: Central Gatekeeper in Inflammation and Immunity

Abstract

Inappropriate functioning of the immune system is linked to immune deficiency, autoimmune disease, and cancer. It is therefore not surprising that intracellular immune signaling pathways are tightly controlled. One of the best studied transcription factors in immune signaling is NF-B, which is activated by multiple receptors and regulates the expression of a wide variety of proteins that control innate and adaptive immunity. A20 is an early NF-B-responsive gene that encodes a ubiquitin-editing protein that is involved in the negative feedback regulation of NF-B signaling. Here, we discuss the mechanism of action of A20 and its role in the regulation of inflammation and immunity. A20 (also known as TNFAIP3) was originally identified as a TNF 2 -inducible gene in human umbilical vein endothelial cells (1). Subsequent research demonstrated that A20 is also induced in many other cell types and by a wide range of other stimuli (reviewed in Ref. 2). Although A20 was originally characterized as an inhibitor of TNF-induced apoptosis (3), it has been most intensively studied as an inhibitor of NF-B activation. NF-B is a dimeric transcription factor that plays a key role in inflammation and immunity. A deregulated NF-B response has been associated with several autoimmune diseases and some cancers (4). The activity of NF-B is tightly regulated by interaction with inhibitory IB (inhibitor of B) proteins, which are regulated by IKK-mediated IB phosphorylation, followed by their ubiquitination and proteolysis, enabling the entry of NF-B into the nucleus. In most cases, the activation of NF-B is transient and cyclic upon continuous stimulation, which is due to specific negative feedback control systems such as the NF-Binducible synthesis of IB and A20 proteins (5). NF-B activation pathways are broadly classified as either canonical or noncanonical, depending on whether activation involves IB degradation or processing of the p100 NF-B precursor (4).The canonical pathway, which is the predominant NF-B signaling pathway, is activated by pro-inflammatory cytokines such as TNF and IL-1 and microbial components that activate, for example, TLRs or antigen receptors. The non-canonical pathway of NF-B activation operates mainly in B cells in response to a subset of TNFR family members, including the lymphotoxin-␤ receptor.Initial evidence for the NF-B inhibitory function of A20 came from several studies in which overexpression of A20 was shown to prevent NF-B activation in response to TNF and several other pro-inflammatory stimuli (reviewed in Ref.2). The observation that A20 expression is itself under the control of NF-B suggested its involvement in the negative feedback regulation of NF-B activation (6). This was eventually confirmed by the generation of A20-deficient mice, which show a sustained NF-B response and severe inflammation (7). The mechanism by which A20 inhibits NF-B activation remained a mystery for several years until it was recently found that A20 can act as a dual ubiquitin-editing enzyme.

A20 suppresses inflammatory responses and bone destruction in human fibroblast‐like synoviocytes and in mice with collagen‐induced arthritis

“…In an inflammatory setting, cells must express antiinflammatory genes as a mechanism to counteract the physiologic stresses that otherwise lead to cellular damage. A20 is a typical example of this self-protecting feedback loop (11). In the present study, we further validated this paradigm using CIA arthritic mice.…”

“…The zinc-finger protein A20 is encoded by an immediate early response gene and acts as a potent inhibitor of the NF-B signaling pathway (11). Interestingly, the expression of A20 is itself under the control of NF-B, suggesting that A20 is involved in the negative-feedback regulation of NF-B activation (11). A20-deficient mice develop severe inflammation, which includes inflammation of the joints (12).…”

Suppression of systemic autoimmunity by the innate immune adaptor STING

“…Therefore, the exacerbated disease phenotype of the STING-deficient MRL/lpr mice likely results from the failure to constrain aberrantly activated TLR signaling cascades responsible for disease. Intriguingly, A20-, SOCS1-, or SOCS3-deficient mice exhibit phenotypes similar to our STING/lpr mice (30,31). In addition to impaired expression of these negative regulators of TLR activation, STING/lpr mice also failed to express the secreted immunosuppressive protein IDO-1.…”

HIV-1 Nef-associated Factor 1 Enhances Viral Production by Interacting with CRM1 to Promote Nuclear Export of Unspliced HIV-1 gag mRNA

“…Naf1 associates with A20, a zinc finger protein with deubiquitinase activity, and facilitates A20-mediated de-ubiquitination of NEMO/IKK␥ and subsequent NF-B inhibition in response of TNF-␣ (40,54,56). HIV-1-LTR contains the NF-B binding sites, and the suppression of Naf1 on NF-B activation may account for the inhibition of HIV-1 promoter LTR-driven gene expression and viral infection.…”