RNase L activates the NLRP3 inflammasome during viral infections

Cell Host Microbe. 2015 Apr 8;17(4):466-77. doi: 10.1016/j.chom.2015.02.010. Epub 2015 Mar 26.


The NLRP3 inflammasome assembles in response to danger signals, triggering self-cleavage of procaspase-1 and production of the proinflammatory cytokine IL-1β. Although virus infection activates the NLRP3 inflammasome, the underlying events remain incompletely understood. We report that virus activation of the NLRP3 inflammasome involves the 2',5'-oligoadenylate (2-5A) synthetase(OAS)/RNase L system, a component of the interferon-induced antiviral response that senses double-stranded RNA and activates endoribonuclease RNase L to cleave viral and cellular RNAs. The absence of RNase L reduces IL-1β production in influenza A virus-infected mice. RNA cleavage products generated by RNase L enhance IL-1β production but require the presence of 2',3'-cyclic phosphorylated termini characteristic of RNase L activity. Additionally, these cleavage products stimulate NLRP3 complex formation with the DExD/H-box helicase, DHX33, and mitochondrial adaptor protein, MAVS, which are each required for effective NLRP3 inflammasome activation. Thus, RNA cleavage events catalyzed by RNase L are required for optimal inflammasome activation during viral infections.

Publication types

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

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Line
  • Endoribonucleases / metabolism*
  • Humans
  • Inflammasomes / metabolism*
  • Influenza A Virus, H1N1 Subtype / immunology*
  • Male
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Orthomyxoviridae Infections / immunology*
  • Orthomyxoviridae Infections / virology


  • Carrier Proteins
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Endoribonucleases
  • 2-5A-dependent ribonuclease