Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome

Nature. 2019 Jun;570(7761):338-343. doi: 10.1038/s41586-019-1295-z. Epub 2019 Jun 12.


The NLRP3 inflammasome can be activated by stimuli that include nigericin, uric acid crystals, amyloid-β fibrils and extracellular ATP. The mitotic kinase NEK7 licenses the assembly and activation of the NLRP3 inflammasome in interphase. Here we report a cryo-electron microscopy structure of inactive human NLRP3 in complex with NEK7, at a resolution of 3.8 Å. The earring-shaped NLRP3 consists of curved leucine-rich-repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 is confirmed by mutagenesis both in vitro and in cells. Modelling of an active NLRP3-NEK7 conformation based on the NLRC4 inflammasome predicts an additional contact between an NLRP3-bound NEK7 and a neighbouring NLRP3. Mutations to this interface abolish the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. These data suggest that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Cryoelectron Microscopy*
  • Humans
  • Inflammasomes / chemistry
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Inflammasomes / ultrastructure*
  • Models, Molecular
  • Mutation
  • NIMA-Related Kinases / chemistry
  • NIMA-Related Kinases / deficiency
  • NIMA-Related Kinases / metabolism*
  • NIMA-Related Kinases / ultrastructure*
  • NLR Family, Pyrin Domain-Containing 3 Protein / chemistry
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / ultrastructure*
  • Protein Binding
  • Protein Domains
  • Protein Multimerization
  • Protein Structure, Quaternary


  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • NEK7 protein, human
  • NIMA-Related Kinases