NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component

Hexin Shi, Ying Wang, Xiaohong Li, Xiaoming Zhan, Miao Tang, Maggy Fina, Lijing Su, David Pratt, Chun Hui Bu, Sara Hildebrand, Stephen Lyon, Lindsay Scott, Jiexia Quan, Qihua Sun, Jamie Russell, Stephanie Arnett, Peter Jurek, Ding Chen, Vladimir V. Kravchenko, John C. MathisonEva Marie Y Moresco, Nancy L. Monson, Richard J. Ulevitch, Bruce Beutler

Research output: Contribution to journalArticle

207 Scopus citations

Abstract

The NLRP3 inflammasome responds to microbes and danger signals by processing and activating proinflammatory cytokines, including interleukin 1β (IL-1β) and IL-18. We found here that activation of the NLRP3 inflammasome was restricted to interphase of the cell cycle by NEK7, a serine-threonine kinase previously linked to mitosis. Activation of the NLRP3 inflammasome required NEK7, which bound to the leucine-rich repeat domain of NLRP3 in a kinase-independent manner downstream of the induction of mitochondrial reactive oxygen species (ROS). This interaction was necessary for the formation of a complex containing NLRP3 and the adaptor ASC, oligomerization of ASC and activation of caspase-1. NEK7 promoted the NLRP3-dependent cellular inflammatory response to intraperitoneal challenge with monosodium urate and the development of experimental autoimmune encephalitis in mice. Our findings suggest that NEK7 serves as a cellular switch that enforces mutual exclusivity of the inflammasome response and cell division.

Original languageEnglish (US)
JournalNature Immunology
DOIs
StateAccepted/In press - Dec 7 2015

ASJC Scopus subject areas

  • Immunology

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    Shi, H., Wang, Y., Li, X., Zhan, X., Tang, M., Fina, M., Su, L., Pratt, D., Bu, C. H., Hildebrand, S., Lyon, S., Scott, L., Quan, J., Sun, Q., Russell, J., Arnett, S., Jurek, P., Chen, D., Kravchenko, V. V., ... Beutler, B. (Accepted/In press). NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nature Immunology. https://doi.org/10.1038/ni.3333