STING-dependent translation inhibition restricts RNA virus replication.

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.

• Authors: Kate M Franz, William J Neidermyer, Yee-Joo Tan, Sean P J Whelan, Jonathan C Kagan
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 9 Pg. E2058-E2067 (02 27 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29440426 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Ligands
• Membrane Proteins
• RNA, Messenger
• Sting1 protein, mouse
• Interferons
• Cyclic GMP

Topics

• Animals
• Autophagy
• Cyclic GMP (metabolism)
• DNA, Mitochondrial (metabolism)
• Fibroblasts (metabolism)
• Gene Expression Regulation
• Genome, Viral
• Interferons (metabolism)
• Ligands
• Membrane Proteins (metabolism)
• Mice
• Mitochondria (metabolism)
• Polyribosomes (metabolism)
• RNA Viruses (physiology)
• RNA, Messenger (metabolism)
• Signal Transduction
• Transcription, Genetic
• Vesicular stomatitis Indiana virus (physiology)
• Virus Replication