NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation

Cell. 2021 Dec 22;184(26):6299-6312.e22. doi: 10.1016/j.cell.2021.11.011. Epub 2021 Dec 2.

Abstract

The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here, we report that an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to 16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for many NLRP3-activating stimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutants abolish inflammasome punctum formation, caspase-1 processing, and cell death. Thus, our data uncover a physiological NLRP3 oligomer on the membrane that is poised to sense diverse signals to induce inflammasome activation.

Keywords: NEK7; NLRP3; TGN; TGN dispersion; cryo-EM; inflammasome; innate immunity; trans-Golgi network.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Membrane / metabolism
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Humans
  • Inflammasomes / metabolism*
  • Mice
  • Models, Biological
  • Models, Molecular
  • Mutation / genetics
  • NIMA-Related Kinases / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / chemistry*
  • NLR Family, Pyrin Domain-Containing 3 Protein / isolation & purification
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / ultrastructure
  • Nigericin / pharmacology
  • Protein Binding
  • Protein Domains
  • Protein Multimerization
  • trans-Golgi Network / metabolism

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NIMA-Related Kinases
  • Nek7 protein, mouse
  • Nigericin