Inflammasomes are activated in response to various microbial or damage-associated signals, which leads to the release of pyrogenic IL-1β. In Molecular Cell, Yuan and colleagues show that the inflammasome component NLRP3 is regulated by ubiquitin modification. Pharmacological inhibitors of deubiquitinase block NLRP3-dependent activation of caspase-1 and secretion of IL-1β in activated macrophages, but NLRC4- or AIM2-dependent inflammasomes are unaffected by such treatment. Ubiquitin Lys48 and Lys63 chains decorate the NACHT and leucine-rich repeat domains of NLRP3, but the stability of NLRP3 protein does not seem to be affected. These ubiquitin modifications must be removed before assembly of the inflammasome with ASC and pro-caspase-1. The deubiquitinase BRCC3 can activate NLRP3 by removing ubiquitin chains in vitro. Knockdown of BRCC3 by small interfering RNA in activated macrophages prevents NLRP3 inflammasome–mediated release of IL-1β. These findings point to another level of regulation of NLRP3 inflammasome activity that potentially can be targeted therapeutically.

Mol. Cell (11 December 2012) doi:10.1016/j.molcel.2012.11.009