A20: linking a complex regulator of ubiquitylation to immunity and human disease

Abstract

A20 (also known as TNFAIP3) is a potent anti-inflammatory signalling molecule that restricts multiple intracellular signalling cascades. Recent studies in three general areas have converged to highlight the clinical and biological importance of A20. First, human genetic studies have strongly linked polymorphisms and mutations in the gene encoding A20 to inflammatory, autoimmune and malignant diseases. Second, studies in gene-targeted mice have revealed that A20 regulates multiple immune cell functions and prevents experimental diseases that closely mimic human conditions. Third, biochemical studies have unveiled complex mechanisms by which A20 regulates ubiquitin-dependent nuclear factor-κB and cell-survival signals. Taken together, these studies are revealing the importance of A20-mediated regulation of ubiquitin-dependent signalling in human disease.

Deubiquitylases From Genes to Organism

“…A20-deficient B cells show hypersensitivity to stimuli of the NF B pathway and increased survival of germinal center B cells. This provides a framework for understanding the role of A20 in suppressing B-cell lymphomas, which is suggested by human genetic studies (36,96,161). Other studies have found critical functions for A20 in dendritic cells (83,126), macrophages (167), and intestinal epithelial cells (265).…”

“…Germ-line single-nucleotide polymorphisms of A20 in humans have been linked with susceptibility to a number of inflammatory conditions, including systemic lupus erythematosus, rheumatoid arthritis, and Crohn's disease (161). The widespread inflammation and perinatal mortality of A20-deficient mice has spurred the generation of lineage-specific, conditional knockout models that allow functional analysis in specific cell types.…”

“…Despite structural conservation within the catalytic domain, the family shows diverse specificity for ubiquitin chain linkages (TABLE 2). The strongest vein of biological data for this family, which has been reviewed extensively elsewhere (34), links the OTU protein A20 (also known as TNFAIP3) to regulation of the proinflammatory NF B pathway (88,161,236). The A20 gene can be induced by NF B signaling and operates within a negative-feedback loop to restrict the duration or intensity of signaling.…”

Role and therapeutic value of dendritic cells in central nervous system autoimmunity

“…One important regulator of NF-kB is the A20 ubiquitin-editing enzyme. 94 A20 catalyzes the removal of K63 linked poly ubiquitin chains (which activate signaling) and the addition of K48 poly ubiquitin chains, which promote proteasomal degradation. A20 controls the ubiquitination of several proteins involved in NF-kB signaling and regulation, actively limiting NF-kBdependent signaling.…”

“…Consequently, A20-deficient DCs are hyper-responsive to stimulation, and mice with a specific deletion of A20 in DCs show an accumulation of activated T cells and develop spontaneous autoimmunity. 95,96 Notably, A20 polymorphisms are also associated with human autoimmune disease, 94 highlighting the physiological relevance of NF-kB regulatory pathways for DC function.…”