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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Caspase 1
  • Chromatography, Gel
  • Colony-Forming Units Assay
  • Cytokines
  • Cytoskeletal Proteins
  • Dendritic Cells
  • Encephalomyelitis, Autoimmune, Experimental / immunology
  • Female
  • Flow Cytometry
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • In Vitro Techniques
  • Inflammasomes / genetics
  • Inflammasomes / immunology
  • Macrophages / immunology*
  • Macrophages, Peritoneal / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / metabolism
  • Mitosis / immunology*
  • Monocytes
  • NIMA-Related Kinases
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology*
  • Reactive Oxygen Species
  • Spinal Cord / immunology

Substances

  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytokines
  • Cytoskeletal Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • Nlrp3 protein, mouse
  • PYCARD protein, human
  • Pycard protein, mouse
  • Reactive Oxygen Species
  • NEK7 protein, human
  • NIMA-Related Kinases
  • Nek7 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Caspase 1