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.
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Visan, I. A20 inhibits the inflammasome. Nat Immunol 16, 228 (2015). https://doi.org/10.1038/ni.3114
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DOI: https://doi.org/10.1038/ni.3114