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Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):E2058-E2067. doi: 10.1073/pnas.1716937115. Epub 2018 Feb 12.

STING-dependent translation inhibition restricts RNA virus replication.

Author information

1
Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.
2
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115.
3
Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117545.
4
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore 138673.
5
Division of Gastroenterology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; Jonathan.Kagan@childrens.harvard.edu.

Abstract

In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I-like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP-AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses.

KEYWORDS:

RIG-I; STING; cGAS; interferon; translation

PMID:
29440426
PMCID:
PMC5834695
DOI:
10.1073/pnas.1716937115
[Indexed for MEDLINE]
Free PMC Article

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