A20: attractive without showing cleavage

Abstract

A20 (also known as TNFAIP3) is a deubiquitinating enzyme (DUB) that ensures optimal immune responses in cells stimulated by cytokines, such as TNF and IL-1, or pathogen components, such as lipopolysaccharide. Deletion of A20 in mice results in multi-organ inflammation and death within 2 weeks . The anti-inflammatory functions of A20 have been attributed to its ability to negatively regulate NF-κB signaling . The picture that has emerged over the last decade is that A20 attenuates NF-κB signaling by removing polyubiquitin chains from specific NF-κB signaling proteins. A study published in this issue of EMBO reports by Sankar Ghosh and colleagues now shows that A20 knockin mice expressing a catalytically inactive A20 mutant that can no longer remove ubiquitin are normal and do not have an inflammatory phenotype. These results challenge the notion that A20 exerts its NF-κB inhibitory and anti-inflammatory function by acting as a DUB.

Figure 1. Domain structure of A20 and associated activities

A20 has an N-terminal ovarian tumor (OTU) domain that mediates DUB activity. C103, which is critical for DUB activity, is indicated by an asterisk. The C-terminal region contains seven ZF motifs that bind multiple proteins implicated in NF-κB signaling. In addition, ZF4 and ZF7 bind distinct mono- and polyubiquitin species and have been suggested to contribute to the negative regulation of NF-κB signaling through multiple mechanisms.