Trends in Immunology
Volume 35, Issue 1, January 2014, Pages 22-31
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Review
A20 in inflammation and autoimmunity

https://doi.org/10.1016/j.it.2013.10.005Get rights and content

Highlights

  • A20 (TNFAIP3) functions are cell-type dependent.

  • A20 exerts its activities via multiple mechanisms including ubiquitin editing.

  • A20 expression and activity is regulated transcriptionally and post-transcriptionally.

  • Human genetic studies have identified A20 as a disease susceptibility gene.

  • Gene targeting studies confirm the crucial role of A20 in controlling tissue homeostasis.

Although known for many years as a nuclear factor (NF)-κB inhibitory and antiapoptotic signaling protein, A20 has recently attracted much attention because of its ubiquitin-regulatory activities and qualification by genome-wide association studies (GWASs) as a susceptibility gene for inflammatory disease. Here, we review new findings that have shed light on the molecular and biochemical mechanisms by which A20 regulates inflammatory signaling cascades, and discuss recent experimental evidence characterizing A20 as a crucial gatekeeper preserving tissue homeostasis.

Section snippets

A20: the early years

The transcription factor NF-κB (Box 1) comprises a family of transcription factors critical for inflammatory signaling, and innate and adaptive immunity. NF-κB also controls the expression of antiapoptotic genes important for cell survival, and plays diverse roles in development, proliferation, cell differentiation, and metabolism [1]. NF-κB activation is central to many cellular processes, therefore, tight regulation of NF-κB signaling pathways is an absolute requirement. Several regulatory

A20 inhibits activation of NF-κB via multiple mechanisms

The molecular mechanisms by which A20 controls its multiple activities are not fully understood and are the subject of intense research. However, the ability of A20 to modulate ubiquitin-dependent signaling cascades has been shown to be of central importance to many of its functions (Table 1).

NF-κB signaling cascades are heavily controlled by ubiquitination, and several proteins including A20 may interfere with these processes (Box 2) [13]. The first evidence for a role for A20 in

Varied roles for A20 in cell death processes

Independent from its role as a modulator of NF-κB signaling, A20 functions as an antiapoptotic protein in several cell types. Whether these functions are dependent on ubiquitin-dependent mechanisms similar to those described above remains elusive. Death receptors induce apoptotic signaling by recruiting adaptor proteins, together assembling the so-called death-inducing signaling complex (DISC). Interestingly, A20 was identified as part of the DISC, where it physically interacts with caspase-8

Modulation of the innate immune response to pathogens

In addition to its role in the NF-κB pathway, A20 functions to regulate IRF activation in response to pathogen recognition (Figure 1). Retinoic acid-inducible gene 1 M (RIG-I) and melanoma differentiation-associated protein 5 (Mda5) are PRRs that recognize viral nucleic acids and activate a pathway involving the mitochondrial adaptor protein mitochondrial antiviral-signaling protein [MAVS; also known as virus-induced signaling adapter IPS-1 (VISA), interferon-beta promoter stimulator 1 (IPS-1)

Mechanisms that regulate A20 function

A20 expression and activity are subject to tight regulation [41]. Most cells express only low amounts of A20 under basal conditions, but A20 expression is rapidly induced upon NF-κB activation due to the presence of two NF-κB binding sites in the A20 promoter. Lymphocytes, however, constitutively express high levels of A20. Antigen receptor stimulation leads to a rapid decrease and subsequent reappearance of A20, suggesting that A20 removal is important in order to allow optimal NF-κB

A20 as a disease susceptibility gene

Multiple studies over the past few years, mostly based on GWASs on genetic material from large cohorts of patients, have identified A20/TNFAIP3 as a susceptibility locus for human inflammatory and autoimmune pathology, including rheumatoid arthritis (RA) and juvenile idiopathic arthritis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), coeliac disease, psoriasis, type I diabetes, Sjogren's syndrome, coronary artery disease, rheumatic heart disease, and systemic sclerosis

Conditional gene targeting studies in mice

Mice deficient for A20 die prematurely due to severe multiorgan inflammation [7], impeding the in vivo study of A20 in adults and in specific disease pathologies. In order to assess the function of A20 in different cell types and in various models of human disease, we and others developed mice with a conditional A20 allele, allowing tissue-specific deletion of A20 37, 68, 69 (Figure 2).

Concluding remarks

A20 is now widely accepted as a key regulator of inflammation and immunity based on its activities on the NF-κB and IRF pathways, as well as its role in protecting from apoptosis. It is likely that future studies will reveal additional roles for A20 in the regulation of signaling pathways. Recent in vivo gene targeting studies have clearly demonstrated an important function for A20 in multiple cell types including myeloid cells, DCs, B cells, keratinocytes, and IECs. These have provided

Acknowledgments

L. Catrysse is a PhD fellow with the “Institute for the Promotion of Innovation by Science and Technology” (IWT) and L. Vereecke is a postdoctoral researcher with the “Fund for Scientific Research of Flanders” (FWO). Research in the authors’ laboratory is supported by an FWO Odysseus Grant and by research grants from the “Geneeskundige Stichting Koningin Elisabeth” (GSKE), the Charcot Foundation, the “Interuniversity Attraction Poles program” (IAP7/32), the FWO, the “Belgian Foundation against

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