A20 ubiquitin binding, not its catalytic activity, is important in Rheumatoid Arthritis (RA)

Introduction

A20, or tumor necrosis factor α-induced protein 3 (TNFAIP3), is a zinc finger ubiquitin editing anti-inflammatory enzyme that modulates immune responses and apoptosis. Mutations in A20 and A20 haploinsufficiency have been linked to several autoimmune and autoinflammatory diseases^1-4, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriatic arthritis^5-7. Studies utilizing animal models have confirmed roles for A20 in the pathogenesis of autoinflammatory and RA-like diseases and helped to identify the mechanisms involved^{8, 9}. The first identified mechanism by which A20 exerts its anti-inflammatory effect was through the inhibition of NF-κB activation¹⁰. Additional mechanisms by which the enzymatic function of A20 offers protection for autoinflammatory conditions have been reported, including inhibition of necroptosis by deubiquitinating receptor-interacting protein kinase 3 (RIPK3)¹¹ (See Figure 1).

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammatory arthritis and a variety of systemic manifestations. The addition of immunosuppressant biologics to classic disease-modifying antirheumatic drugs (DMARDs) has improved the management of RA¹². However, there is no cure, and the underlying mechanisms of disease pathogenesis remain to be fully elucidated. In recent years, two ubiquitin-binding domains, zinc finger 4 (ZnF4) and ZnF7, in the A20 protein have been shown to be essential for inhibiting inflammation-dependent arthritis^{9, 13}. This newsletter will review evidence that unveiled the importance of A20 ubiquitin-binding in RA and related arthritic disorders.  

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Also included in this newsletter:

• Actin and Microtubule Tools
• Related Publications