Xu Jie, Zhang Lingzhi, Duan Yanhui, Sun Fangyuan, Odeh Nouha, He Yuan, Núñez Gabriel
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Department of Biochemistry, Microbiology and Immunology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Sci Immunol. 2025 Jan 3;10(103):eadl2993. doi: 10.1126/sciimmunol.adl2993.
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 Thr and Thr 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.
NLRP3炎性小体在固有免疫和炎症性疾病中起关键作用。NIMA相关激酶7（NEK7）对炎性小体激活至关重要，钾离子外流增强了其与NLRP3的相互作用。然而，钾离子外流促进这种相互作用的机制仍不清楚。在此，我们表明，NLRP3激活后，NEK7在钾离子外流和gasdermin D（GSDMD）下游被JNK1迅速磷酸化在苏氨酸-190/191位点。NEK7磷酸化增强了NEK7与NLRP3之间的结合，进而促进炎性小体组装和激活。Nek7的苏氨酸被缬氨酸取代的突变小鼠和巨噬细胞表现出NEK7磷酸化受损、NLRP3炎性小体激活受损和IL-1β分泌受损。因此，NEK7磷酸化是钾离子外流和GSDMD下游的一个重要事件，可进一步增强NLRP3炎性小体激活。
