Parsing the role of NSP1 in SARS-CoV-2 infection

Tal Fisher; Avi Gluck; Krishna Narayanan; Makoto Kuroda; Aharon Nachshon; Jason C. Hsu; Peter J. Halfmann; Yfat Yahalom-Ronen; Hadas Tamir; Yaara Finkel; Michal Schwartz; Shay Weiss; Chien Te K. Tseng; Tomer Israely; Nir Paran; Yoshihiro Kawaoka; Shinji Makino; Noam Stern-Ginossar

doi:10.1016/j.celrep.2022.110954

Parsing the role of NSP1 in SARS-CoV-2 infection

Tal Fisher, Avi Gluck, Krishna Narayanan, Makoto Kuroda, Aharon Nachshon, Jason C. Hsu, Peter J. Halfmann, Yfat Yahalom-Ronen, Hadas Tamir, Yaara Finkel, Michal Schwartz, Shay Weiss, Chien Te K. Tseng, Tomer Israely, Nir Paran, Yoshihiro Kawaoka, Shinji Makino, Noam Stern-Ginossar

Research output: Contribution to journal › Article › peer-review

36 Scopus citations

Abstract

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.

Original language	English
Article number	110954
Journal	Cell Reports
Volume	39
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2022.110954
State	Published - 14 Jun 2022
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2022 The Authors

Funding

We thank Igor Ulitsky and Schraga Schwartz for providing valuable feedback. We also thank Dr. Steve Widen at UTMB's Next Generation Sequencing Core for technical assistance. This work was supported by Public Health Service grant AI146081 from the National Institutes of Health and pilot grants from the Institute for Human Infections and Immunity at The University of Texas Medical Branch to S.M.; by the National Institute of Allergy and Infectious Diseases and the Center for Research on Influenza Pathogenesis (HHSN272201400008C), Research Program on Emerging and Re-emerging Infectious Diseases (JP20fk0108412), and the Japan Program for Infectious Diseases Research and Infrastructure (JP21wm0125002) from the Japan Agency for Medical Research and Development (AMED) to Y.K.; and by research grants from the Weizmann Corona Response Fund, the Knell Family Center for Microbiology, a research grant from the Weizmann SABRA - Yeda-Sela - WRC Program, the Estate of Emile Mimran and The Maurice and Vivienne Wohl Biology Endowment to N.S.-G. T.F. A.G. K.N. N.S.-G. S.M. N.P. and Y.K. conceptualized the study; T.F. A.G. K.N. M.K. M.S. J.C.H. P.J.H. Y.Y.-R. H.T. S.W. C.-T.K.T. T.I. and N.P. performed experiments; T.F. A.G. A.N. K.N. M.K. J.C.H. P.J.H. C.-T.K.T. and Y.F. analyzed the data; and S.M. K.N. M.K. M.S. C.-T.K.T. N.S.-G. T.F. and A.G. wrote the manuscript with contribution from all other authors. The authors declare no competing interests.

Funders	Funder number
Institute for Human Infections and Immunity at The University of Texas Medical Branch
Japan Program for Infectious Diseases Research and Infrastructure	JP21wm0125002
Maurice and Vivienne Wohl Biology Endowment
Weizmann Corona Response Fund
National Institutes of Health
National Institute of Allergy and Infectious Diseases	HHSN272201400008C, R01AI146081, JP20fk0108412
U.S. Public Health Service
Japan Agency for Medical Research and Development

Keywords

CP: Microbiology
Coronaviruses
Host shutoff
Interferon
Nsp1
RNA
SARS-CoV-2
Translation regulation

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10.1016/j.celrep.2022.110954

Cite this

Fisher, T., Gluck, A., Narayanan, K., Kuroda, M., Nachshon, A., Hsu, J. C., Halfmann, P. J., Yahalom-Ronen, Y., Tamir, H., Finkel, Y., Schwartz, M., Weiss, S., Tseng, C. T. K., Israely, T., Paran, N., Kawaoka, Y., Makino, S., & Stern-Ginossar, N. (2022). Parsing the role of NSP1 in SARS-CoV-2 infection. Cell Reports, 39(11), Article 110954. https://doi.org/10.1016/j.celrep.2022.110954

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Parsing the role of NSP1 in SARS-CoV-2 infection

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