SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses

Banerjee, A. K. et al. (2020) SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell, (doi: 10.1016/j.cell.2020.10.004) (PMID:33080218) (PMCID:PMC7543886)

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a recently identified coronavirus that causes the respiratory disease known as coronavirus disease 2019 (COVID-19). Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis. Here, we comprehensively define the interactions between SARS-CoV-2 proteins and human RNAs. NSP16 binds to the mRNA recognition domains of the U1 and U2 splicing RNAs and acts to suppress global mRNA splicing upon SARS-CoV-2 infection. NSP1 binds to 18S ribosomal RNA in the mRNA entry channel of the ribosome and leads to global inhibition of mRNA translation upon infection. Finally, NSP8 and NSP9 bind to the 7SL RNA in the signal recognition particle and interfere with protein trafficking to the cell membrane upon infection. Disruption of each of these essential cellular functions acts to suppress the interferon response to viral infection. Our results uncover a multipronged strategy utilized by SARS-CoV-2 to antagonize essential cellular processes to suppress host defenses.

• Item Type: Articles
• Additional Information: This work was supported by NIH F30HL136080 (to A.K.B.); P20GM125498 and P30GM118228-04 (to E.A.B.); NIH GM7616-40 and F30CA247447 (to P.B.); UM1HL120877 and U54GM115516 (to D.M.); R41AI132047 and U01AI1141997 (to J.W.B.); U01 DA040612 and U01 HL130007 (to M.G.); the USC MD/PhD Program (to A.K.B.); UCLA-Caltech MSTP (to P.B.); American Cancer Society PF-17-240-01 (to N.O.); Wellcome Trust 201366/Z/16/Z (to S.J.R.); the Office of the Vice President for Research at UVM (to J.W.B.); Heritage Medical Research Institute (to M.G. and R.V.); and NYSCF, CZI, and Caltech (to M.G.). M.G. is a NYSCF-Robertson Investigator.
• Keywords: SARS-CoV-2, RNA-protein interactions, NSP1, NSP8, NSP9, NSP16, interferon, mRNA splicing, translation, protein trafficking.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Goldfarb, Daniel Max and De Lorenzo, Dr Giuditta and Rihn, Dr Suzannah and Loney, Mr Colin and Stewart, Mr Douglas
• Authors: Banerjee, A. K., Blanco, M. R., Bruce, E. A., Honson, D. D., Chen, L. M., Chow, A., Bhat, P., Ollikainen, N., Quinodoz, S. A., Loney, C., Thai, J., Miller, Z. D., Lin, A. E., Schmidt, M. M., Stewart, D. G., Goldfarb, D., De Lorenzo, G., Rihn, S. J., Voorhees, R. M., Botten, J. W., Majumdar, D., and Guttman, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Cell
• Publisher: Elsevier (Cell Press)
• ISSN: 0092-8674
• ISSN (Online): 1097-4172
• Published Online: 08 October 2020
• Copyright Holders: Copyright © 2020 The Authors
• First Published: First published in Cell 2020
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
173514		Inhibition of HIV-1 by Type II Interferon	Suzannah Rihn	Wellcome Trust (WELLCOTR)	201366/Z/16/Z	III - Centre for Virus Research