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

Microbiology And Immunology

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

35 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 (US)
Article number	110954
Journal	Cell Reports
Volume	39
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2022.110954
State	Published - Jun 14 2022

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.celrep.2022.110954

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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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AU - Gluck, Avi

AU - Narayanan, Krishna

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AU - Nachshon, Aharon

AU - Hsu, Jason C.

AU - Halfmann, Peter J.

AU - Yahalom-Ronen, Yfat

AU - Tamir, Hadas

AU - Finkel, Yaara

AU - Schwartz, Michal

AU - Weiss, Shay

AU - Tseng, Chien Te K.

AU - Israely, Tomer

AU - Paran, Nir

AU - Kawaoka, Yoshihiro

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AU - Stern-Ginossar, Noam

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

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