RNA viruses promote activation of the NLRP3 inflammasome through a RIP1-RIP3-DRP1 signaling pathway

Nat Immunol. 2014 Dec;15(12):1126-33. doi: 10.1038/ni.3015. Epub 2014 Oct 19.


The NLRP3 inflammasome functions as a crucial component of the innate immune system in recognizing viral infection, but the mechanism by which viruses activate this inflammasome remains unclear. Here we found that inhibition of the serine-threonine kinases RIP1 (RIPK1) or RIP3 (RIPK3) suppressed RNA virus-induced activation of the NLRP3 inflammasome. Infection with an RNA virus initiated assembly of the RIP1-RIP3 complex, which promoted activation of the GTPase DRP1 and its translocation to mitochondria to drive mitochondrial damage and activation of the NLRP3 inflammasome. Notably, the RIP1-RIP3 complex drove the NLRP3 inflammasome independently of MLKL, an essential downstream effector of RIP1-RIP3-dependent necrosis. Together our results reveal a specific role for the RIP1-RIP3-DRP1 pathway in RNA virus-induced activation of the NLRP3 inflammasome and establish a direct link between inflammation and cell-death signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / immunology*
  • Cell Line
  • Dynamins / immunology
  • Enzyme-Linked Immunosorbent Assay
  • GTP Phosphohydrolases / immunology
  • Humans
  • Immunoprecipitation
  • Inflammasomes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Confocal
  • Microtubule-Associated Proteins / immunology
  • Mitochondrial Proteins / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • RNA Virus Infections / immunology*
  • RNA Viruses
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Receptor-Interacting Protein Serine-Threonine Kinases / immunology*
  • Signal Transduction / immunology*
  • Transfection


  • Carrier Proteins
  • Inflammasomes
  • Microtubule-Associated Proteins
  • Mitochondrial Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Small Interfering
  • RIPK1 protein, human
  • RIPK3 protein, human
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • Ripk1 protein, mouse
  • GTP Phosphohydrolases
  • DNM1L protein, human
  • Dnm1l protein, mouse
  • Dynamins