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Nat Immunol. 2016 Mar;17(3):250-8. doi: 10.1038/ni.3333. Epub 2015 Dec 7.

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

Author information

1
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
2
Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
3
Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, California, USA.

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.

Comment in

PMID:
26642356
PMCID:
PMC4862588
DOI:
10.1038/ni.3333
[Indexed for MEDLINE]
Free PMC Article

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