NLRP3 Phosphorylation Is an Essential Priming Event for Inflammasome Activation

Mol Cell. 2017 Oct 5;68(1):185-197.e6. doi: 10.1016/j.molcel.2017.08.017. Epub 2017 Sep 21.


Many infections and stress signals can rapidly activate the NLRP3 inflammasome to elicit robust inflammatory responses. This activation requires a priming step, which is thought to be mainly for upregulating NLRP3 transcription. However, recent studies report that the NLRP3 inflammasome can be activated independently of transcription, suggesting that the priming process has unknown essential regulatory steps. Here, we report that JNK1-mediated NLRP3 phosphorylation at S194 is a critical priming event and is essential for NLRP3 inflammasome activation. We show that NLRP3 inflammasome activation is disrupted in NLRP3-S194A knockin mice. JNK1-mediated NLRP3 S194 phosphorylation is critical for NLRP3 deubiquitination and facilitates its self-association and the subsequent inflammasome assembly. Importantly, we demonstrate that blocking S194 phosphorylation prevents NLRP3 inflammasome activation in cryopyrin-associated periodic syndromes (CAPS). Thus, our study reveals a key priming molecular event that is a prerequisite for NLRP3 inflammasome activation. Inhibiting NLRP3 phosphorylation could be an effective treatment for NLRP3-related diseases.

Keywords: CAPS; JNK1; NLRP3; inflammasome; phosphorylation; priming.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Deubiquitinating Enzymes / genetics
  • Deubiquitinating Enzymes / immunology
  • Escherichia coli / chemistry
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Inflammasomes / genetics*
  • Inflammasomes / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology*
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase 8 / genetics*
  • Mitogen-Activated Protein Kinase 8 / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein / deficiency
  • NLR Family, Pyrin Domain-Containing 3 Protein / genetics*
  • NLR Family, Pyrin Domain-Containing 3 Protein / immunology
  • Phosphorylation
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Shock, Septic / chemically induced
  • Shock, Septic / genetics*
  • Shock, Septic / mortality
  • Shock, Septic / pathology
  • Signal Transduction
  • Survival Analysis


  • Inflammasomes
  • Lipopolysaccharides
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Mitogen-Activated Protein Kinase 8
  • Deubiquitinating Enzymes