NLRP3 inflammasome inhibition is disrupted in a group of auto-inflammatory disease CAPS mutations

Nat Immunol. 2016 Oct;17(10):1176-86. doi: 10.1038/ni.3538. Epub 2016 Aug 22.

Abstract

Inflammasomes are positioned to rapidly escalate the intensity of inflammation by activating interleukin (IL)-1β, IL-18 and cell death by pyroptosis. However, negative regulation of inflammasomes remains poorly understood, as is the signaling cascade that dampens inflammasome activity. We found that rapid NLRP3 inflammasome activation was directly inhibited by protein kinase A (PKA), which was induced by prostaglandin E2 (PGE2) signaling via the PGE2 receptor E-prostanoid 4 (EP4). PKA directly phosphorylated the cytoplasmic receptor NLRP3 and attenuated its ATPase function. We found that Ser295 in human NLRP3 was critical for rapid inhibition and PKA phosphorylation. Mutations in NLRP3-encoding residues adjacent to Ser295 have been linked to the inflammatory disease CAPS (cryopyrin-associated periodic syndromes). NLRP3-S295A phenocopied the human CAPS mutants. These data suggest that negative regulation at Ser295 is critical for restraining the NLRP3 inflammasome and identify a molecular basis for CAPS-associated NLRP3 mutations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / metabolism
  • Animals
  • Cell Line
  • Cryopyrin-Associated Periodic Syndromes / genetics
  • Cryopyrin-Associated Periodic Syndromes / immunology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dinoprostone / metabolism
  • Humans
  • Inflammasomes / metabolism*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Monocytes / physiology*
  • Mutation / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Phenotype
  • Phosphorylation / genetics
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Serine / genetics
  • Signal Transduction / genetics

Substances

  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Receptors, Prostaglandin E, EP4 Subtype
  • Serine
  • Cyclic AMP-Dependent Protein Kinases
  • Adenosine Triphosphatases
  • Dinoprostone