Structural mechanism for NEK7-licensed NLRP3 inflammasome activation

Summary

The NLRP3 inflammasome can be activated by diverse stimuli, including nigericin, uric acid crystals, amyloid-β fibrils, and extracellular ATP. The mitotic kinase NEK7 licenses NLRP3 inflammasome assembly and activation in the interphase. Here we report a 3.8-Å cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7. The earring-shaped NLRP3 consists of curved leucine-rich repeat (LRR) and globular NACHT domains, whereas the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations on this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7 ^KO or NLRP3 ^KO cells. Taken together, these data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate NLRP3 inflammasome activation.