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

RNase L activates the NLRP3 inflammasome during viral infections.

Author information

1
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
2
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Lycera Corporation, Ann Arbor, MI 48109, USA.
3
Department of Immunology, Center for Innate Immunity and Immune Disease, University of Washington School of Medicine, Seattle, WA 98195, USA.
4
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: silverr@ccf.org.

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.

PMID:
25816776
PMCID:
PMC4393362
DOI:
10.1016/j.chom.2015.02.010
[Indexed for MEDLINE]
Free PMC Article

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