Cofilin-1 is a Redox-Sensitive Guard of the NLRP3 Inflammasome

Mutations in NLRP3 cause a spectrum of autoinflammatory disease, cryopyrin-associated periodic syndromes (CAPS). Reactive oxygen species (ROS) play a key role in NLRP3 inflammasome activation. We identified cofilin-1, an actin-severing protein, as a negative regulator of the NLRP3 inflammasome. In resting cells, cofilin-1 directly bound NLRP3, but upon stimulation with NLRP3 inflammasome activators, it was oxidized by ROS and dissociated from NLRP3. CAPS-associated mutant NLRP3 exhibited reduced binding to cofilin-1 compared to wild-type. Residues 101–104 of cofilin-1 were critical for NLRP3 interaction. Oxidation-resistant 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, but not flagellin. Bioinformatic structural analyses corroborate a model in which cofilin-1 plays a pivotal role in NLRP3 activation by ROS and support the potential use of cofilin-1-derived peptides in patients who are unresponsive to or intolerant of other forms of NLRP3 blockade.