文献类型：期刊文献

英文题名：NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux

作者：He, Yuan[1,2];Zeng, Melody Y.[1,2];Yang, Dahai[1,2,3];Metro, Benny[4];Nunez, Gabriel[1,2]

机构：[1]Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA;[2]Univ Michigan, Sch Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA;[3]E China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel

年份：2016

卷号：530

期号：7590

起止页码：354

外文期刊名：NATURE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000370327100041)】；

基金：We thank R. Munoz-Planillo for potassium efflux assays, S. Varadarajan for plasmid construction, L. Burmeister for animal husbandry, J. Whitfield for ELISA assays, and V. Basrur for mass spectrometry analysis. Y.H. was supported by NIH training grant T32HL007517. M.Y.Z. was supported by NIH training grants T32HL007517 and T32DK094775. D.Y. was supported by the State Scholarship Fund from China Scholarship Council (no. 201306740018). This work was supported by NIH grants R01AI063331 and R01DK091191 to G.N., research funds by the Israel Science Foundation (grant no. 768/11) to B.M., and funds to the Michigan Comprehensive Cancer Center Immunology Monitoring Core from the University of Michigan's Cancer Center Support Grant.

语种：英文

摘要：Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases(1). So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1 beta and IL-18 proteins(2,3). The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases(4,5) as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations(6,7). Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli(8,9). Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins)(10), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1 beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7(-/-) or Nlrp3(-/-) haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.