NLRP3 recruitment by NLRC4 during Salmonella infection

J Exp Med. 2016 May 30;213(6):877-85. doi: 10.1084/jem.20132234. Epub 2016 May 2.

Abstract

NLRC4 and NLRP3, of the NOD-like receptor (NLR) family of intracellular proteins, are expressed in innate immune cells and are thought to nucleate distinct inflammasome complexes that promote caspase-1 activation, secretion of the proinflammatory cytokines IL-1β and IL-18, and a form of cell death termed pyroptosis. We show that NLRP3 associates with NLRC4 in macrophages infected with Salmonella typhimurium or transfected with flagellin. The significance of the interaction between the NLRC4 NACHT domain and NLRP3 was revealed when Nlrc4(S533A/S533A) bone marrow-derived macrophages (BMDMs) expressing phosphorylation site mutant NLRC4 S533A had only a mild defect in caspase-1 activation when compared with NLRC4-deficient BMDMs. NLRC4 S533A activated caspase-1 by recruiting NLRP3 and its adaptor protein ASC. Thus, Nlrc4(S533A/S533A) Nlrp3(-/-) BMDMs more closely resembled Nlrc4(-/-) BMDMs in their response to S. typhimurium or flagellin. The interplay between NLRP3 and NLRC4 reveals an unexpected overlap between what had been considered distinct inflammasome scaffolds.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / immunology*
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Cells / microbiology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / immunology*
  • Flagellin / genetics
  • Flagellin / immunology
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Mice
  • Mice, Knockout
  • Mutation, Missense
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
  • Protein Domains
  • Salmonella Infections / genetics
  • Salmonella Infections / immunology*
  • Salmonella typhimurium / genetics
  • Salmonella typhimurium / immunology*

Substances

  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • Ipaf protein, mouse
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Flagellin