Cofilin-1 is a redox-sensitive guard of the NLRP3 inflammasome.

Mutations in NLRP3 can cause a spectrum of the autoinflammatory cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) have a central role in NLRP3 inflammasome activation. Here we show that cofilin-1, an actin-severing protein, is a negative regulator of the NLRP3 inflammasome. In resting cells, cofilin-1 directly bound NLRP3, but after stimulation with NLRP3 inflammasome activators, it was oxidized by ROS and dissociated from NLRP3. CAPS-associated mutant NLRP3 exhibited reduced binding to cofilin-1. Residues 101-104 of cofilin-1 were critical for NLRP3 interaction. Oxidation-independent peptides containing this NLRP3 binding motif suppressed inflammasome activation induced by endogenous CAPS-associated mutations and ex vivo NLRP3 activators such as ATP and nigericin. Bioinformatic structural analyses corroborate a model in which cofilin-1 has a pivotal function in NLRP3 activation by ROS and support the potential use of cofilin-1-derived peptides in individuals who are unresponsive to or intolerant of other forms of NLRP3 blockade.