Structural mechanism for NEK7-licensed NLRP3 inflammasome activation

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.