STING-dependent translation inhibition restricts RNA virus replication

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Interferon (IFN) responses in mammalian cells are activated by distinct pathways for RNA and DNA viruses.
• RIG-I-like receptors (RLRs) sense viral RNA and signal via MAVS, while cGAS senses viral DNA and signals via STING.
• STING is known to mediate IFN expression in response to DNA viruses.

Purpose of the Study:

• To investigate the role of STING in RNA virus infection.
• To elucidate the mechanisms by which STING restricts viral replication.
• To understand the distinct functions of STING in antiviral defense.

Main Methods:

• Confirmation of STING's non-essential role in IFN induction during RNA virus infection.
• Assessment of STING's requirement for restricting diverse RNA virus replication.
• Investigation of STING's antiviral mechanisms using vesicular stomatitis virus (VSV) as a model.
• Analysis of STING's effect on protein synthesis, translation initiation, and gene expression.
• Genetic analysis linking RNA sensing by RLRs to STING-dependent translation inhibition.

Main Results:

• STING is required to restrict the replication of diverse RNA viruses, independent of IFN expression.
• STING's antiviral activity is not linked to regulating basal IFN-stimulated genes, transcription, or autophagy.
• STING inhibits translation initiation during RNA virus infection and upon transfection with RLR ligands.
• STING deficiency leads to a 100-fold increase in susceptibility to productive viral infections.
• RNA sensing by RLRs activates STING-dependent translation inhibition independently of MAVS.

Conclusions:

• STING possesses dual functions in host defense: regulating protein synthesis against RNA viruses and regulating IFN expression against DNA viruses.
• STING plays a critical role in controlling RNA virus replication by inhibiting protein synthesis at the translation initiation level.
• The STING-MAVS pathway is not required for STING-mediated translation inhibition during RNA virus infection.