NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux.

TitleNEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux.
Publication TypeJournal Article
Year of Publication2016
AuthorsHe Y, Zeng MY, Yang D, Motro B, Nunez G
JournalNature
Volume530
Issue7590
Pagination354-7
Date Published2016 Feb 18
ISSN1476-4687
KeywordsAnimals, Apoptosis Regulatory Proteins, Biocatalysis, CARD Signaling Adaptor Proteins, Carrier Proteins, Caspase 1, Catalytic Domain, Cells, Cultured, Cryopyrin-Associated Periodic Syndromes, Enzyme Activation, HEK293 Cells, Humans, Inflammasomes, Interleukin-1beta, Macrophages, Mice, Mice, Inbred C57BL, NIMA-Related Kinases, NLR Family, Pyrin Domain-Containing 3 Protein, Potassium, Protein Binding, Protein Multimerization, Protein-Serine-Threonine Kinases
Abstract

Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. 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-1β and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. 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), 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-1β 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.

DOI10.1038/nature16959
Custom 1

https://www.ncbi.nlm.nih.gov/pubmed/26814970?dopt=Abstract

Alternate JournalNature
PubMed ID26814970
PubMed Central IDPMC4810788
Grant ListR01 DK091191 / DK / NIDDK NIH HHS / United States
T32DK094775 / DK / NIDDK NIH HHS / United States
T32 HL007517 / HL / NHLBI NIH HHS / United States
R37 AI063331 / AI / NIAID NIH HHS / United States
R01AI063331 / AI / NIAID NIH HHS / United States
T32HL007517 / HL / NHLBI NIH HHS / United States
P30 DK034933 / DK / NIDDK NIH HHS / United States
R01 AI063331 / AI / NIAID NIH HHS / United States
R01DK091191 / DK / NIDDK NIH HHS / United States
T32 DK094775 / DK / NIDDK NIH HHS / United States

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