A20: attractive without showing cleavage.

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 [1]. The anti-inflammatory functions of A20 have been attributed to its ability to negatively regulate NF-jB signaling [2]. The picture that has emerged over the last decade is that A20 attenuates NF-jB signaling by removing polyubiquitin chains from specific NF-jB signaling proteins. A study published in this issue of EMBO reports by Sankar Ghosh and colleagues [3] 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-jB inhibitory and antiinflammatory function by acting as a DUB.