Mice with deficient expression of the ubiquitin-modifying enzyme A20 spontaneously develop a systemic inflammatory syndrome. In Immunity, Ma and colleagues show that A20-deficient macrophages secrete the inflammatory cytokine IL-1β in response to stimulation with Toll-like receptor ligands (signal 1) only, while intracellular expression of pro-IL-1β, but not release of mature IL-1β, is observed in wild-type macrophages. The effect is 'rescued' by deletion of components of the NLRP3 inflammasome, such as ASC and caspase-1. Deletion of RIPK3, a kinase involved in the spontaneous activation of NLRP3 in some contexts but independent of A20-mediated regulation of the transcription factor NF-κB, can also 'rescue' this mutant. A20 associates with and inhibits the catalytic activity of a complex containing caspase-1, caspase-8, RIPK1 and RIPK3 and also restricts the Lys63-linked polyubiquitination of pro-IL-1β, a modification that promotes its proteolytic cleavage. Thus, A20 suppresses NLRP3 inflammasomes by various different mechanisms.

Immunity 42, 55–67 (2015)