Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Avi Gluck
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Krishna Narayanan
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA
Makoto Kuroda
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53711, USA
Aharon Nachshon
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Jason C. Hsu
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA
Peter J. Halfmann
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53711, USA
Yfat Yahalom-Ronen
Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 74100, Israel
Hadas Tamir
Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 74100, Israel
Yaara Finkel
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Michal Schwartz
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel
Shay Weiss
Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 74100, Israel
Chien-Te K. Tseng
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA; Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA
Tomer Israely
Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 74100, Israel
Nir Paran
Department of Infectious Diseases, Israel Institute for Biological Research, Ness Ziona 74100, Israel; Corresponding author
Yoshihiro Kawaoka
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53711, USA; Department of Virology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan; The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo 162-8655, Japan; Corresponding author
Shinji Makino
Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA; Institute for Human Infections and Immunity, The University of Texas Medical Branch, Galveston, TX 77555-1019, USA; Corresponding author
Noam Stern-Ginossar
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel; Corresponding author
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to shutoff of protein synthesis, and nsp1, a central shutoff factor in coronaviruses, inhibits cellular mRNA translation. However, the diverse molecular mechanisms employed by nsp1 as well as its functional importance are unresolved. By overexpressing various nsp1 mutants and generating a SARS-CoV-2 mutant, we show that nsp1, through inhibition of translation and induction of mRNA degradation, targets translated cellular mRNA and is the main driver of host shutoff during infection. The propagation of nsp1 mutant virus is inhibited exclusively in cells with intact interferon (IFN) pathway as well as in vivo, in hamsters, and this attenuation is associated with stronger induction of type I IFN response. Therefore, although nsp1’s shutoff activity is broad, it plays an essential role, specifically in counteracting the IFN response. Overall, our results reveal the multifaceted approach nsp1 uses to shut off cellular protein synthesis and uncover nsp1’s explicit role in blocking the IFN response.
