Viruses hijack the host translation machinery to synthesize viral proteins. To compete with the host transcripts for the translation machinery, viruses employ diverse mechanisms to enhance viral translation and inhibit host translation. This selective translation not only ensures efficient synthesis of viral proteins but dampens the antiviral responses by limiting the host protein synthesis. We found that SARS-CoV-2 infection shuts down host translation, and that such activity is largely attributed to the nonstructural protein NSP14. Importantly, we also showed that such translation inhibition function could be an effective viral immune evasion strategy employed by SARS-CoV-2 to subvert the type I interferon (IFN-I) antiviral response. Dr. Hsu's research program will focus on understanding how translational regulations induced by viruses like SARS-CoV-2, Zika virus and eastern equine encephalitis virus play pivotal roles in pathogenesis and viral immune evasion.
SARS-CoV-2 infection shuts down host translation (Hsu et al., 2021, PNAS).
On the flip side, since viruses completely depend on host translation for viral protein synthesis, a common cellular response to viral infection is translation inhibition. IFN-I inhibits global translation to establish an antiviral state in host cells primarily by inducing interferon-stimulated genes (ISGs). In his recently accepted manuscript, we found that the ISG-encoded antiviral protein viperin inhibits the replication of flaviviruses by restricting viral translation. We demonstrated that viperin and its enzymatic product 3'-deoxy-3',4'-didehydro-cytidine triphosphate (ddhCTP) induce ribosome collision-dependent translation inhibition to limit viral replication. However, how viperin/ddhCTP induce ribosome collisions remains unknown. Dr. Hsu's research program will focus on understanding how ribosome collision is induced during the antiviral responses and how such cellular stress benefits host cells against pathogens.
Viperin dampens viral replication by translation inhibition (Hsu et al., 2022, Mol Cell)
At Yale University, Dr. Hsu has set up five technologies for translation studies, including ribosome sequencing (Ribo-seq), polysome profiling, and three systems based on protein and nascent chain labelings: [35S]-methionine metabolic labeling, puromycin labeling and O-propargyl-puromycin (OP-Puro) labeling. Dr. Hsu will establish and employ these tools in his research program to study the above proposed projects and collaborate with experts to investigate translational regulation in their biological systems of interest. Moreover, these technologies will serve as a platform to understand how pathogenic viruses like SARS-CoV-2, Zika virus and eastern equine encephalitis virus shut down host protein synthesis to evade the host antiviral responses.
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