@article{d4190ed7dcdd463fb401f73b144106f1,
title = "Parsing the role of NSP1 in SARS-CoV-2 infection",
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{\textquoteright}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{\textquoteright}s explicit role in blocking the IFN response.",
keywords = "CP: Microbiology, Coronaviruses, Host shutoff, Interferon, Nsp1, RNA, SARS-CoV-2, Translation regulation",
author = "Tal Fisher and Avi Gluck and Krishna Narayanan and Makoto Kuroda and Aharon Nachshon and Hsu, {Jason C.} and Halfmann, {Peter J.} and Yfat Yahalom-Ronen and Hadas Tamir and Yaara Finkel and Michal Schwartz and Shay Weiss and Tseng, {Chien Te K.} and Tomer Israely and Nir Paran and Yoshihiro Kawaoka and Shinji Makino and Noam Stern-Ginossar",
note = "Funding Information: 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. Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = jun,
day = "14",
doi = "10.1016/j.celrep.2022.110954",
language = "English (US)",
volume = "39",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}