title: RNase L activates the NLRP3 inflammasome during viral infections.
abstract: 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.
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Arindam
authors: A
authors: Chakrabarti
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Shuvojit
authors: S
authors: Banerjee
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Lycera Corporation, Ann Arbor, MI 48109, USA.
authors: Luigi
authors: L
authors: Franchi
authors: Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Yueh-Ming
authors: YM
authors: Loo
authors: Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors: Michael
authors: M
authors: Gale
authors: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors: Gabriel
authors: G
authors: Núñez
authors: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: silverr@ccf.org.
authors: Robert H
authors: RH
authors: Silverman
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004722:Endoribonucleases / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease