NEK7 phosphorylation amplifies NLRP3 inflammasome activation downstream of gasdermin D and potassium efflux

The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory disease. The interaction of NEK7, a member of the NIMA-related kinase family that is essential for inflammasome activation, with NLRP3 is enhanced by potassium efflux. However, the mechanism by which potassium efflux promotes the interaction between NEK7 and NLRP3 remains unknown. Here, we show that following NLRP3 activation NEK7 is rapidly phosphorylated at a specific threonine residue by JNK1 downstream of gasdermin D-mediated potassium efflux. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which the threonine residue of NEK7 was replaced by valine were impaired in NEK7 phosphorylation, NLRP3 inflammasome activation and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of gasdermin D and potassium efflux to further enhance NLRP3 inflammasome activation.