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

The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K⁺ efflux. However, the mechanism by which K⁺ efflux promotes this interaction remains unknown. Here, we show that NEK7 is rapidly phosphorylated at threonine-190/191 by JNK1 downstream of K⁺ efflux and gasdermin D (GSDMD) after NLRP3 activation. NEK7 phosphorylation enhances the binding between NEK7 and NLRP3, which further promotes inflammasome assembly and activation. Mutant mice and macrophages in which Thr¹⁹⁰ and Thr¹⁹¹ of Nek7 were replaced by valine exhibited impaired NEK7 phosphorylation, NLRP3 inflammasome activation, and IL-1β secretion. Thus, NEK7 phosphorylation is an important event that acts downstream of K⁺ efflux and GSDMD to further enhance NLRP3 inflammasome activation.