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

Banerjee, Abhik K. and Blanco, Mario R. and Bruce, Emily A. and Honson, Drew D. and Chen, Linlin M. and Chow, Amy and Bhat, Prashant and Ollikainen, Noah and Quinodoz, Sofia A. and Loney, Colin and Thai, Jasmine and Miller, Zachary D. and Lin, Aaron E. and Schmidt, Madaline M. and Stewart, Douglas G. and Goldfarb, Daniel and De Lorenzo, Giuditta and Rihn, Suzannah J. and Voorhees, Rebecca and Botten, Jason W. and Majumdar, Devdoot and Guttman, Mitchell (2020) SARS-CoV-2 disrupts splicing, translation, and protein trafficking to suppress host defenses. Cell, 183 (5). pp. 1325-1339. ISSN 0092-8674. PMCID PMC7543886. https://resolver.caltech.edu/CaltechAUTHORS:20201008-083809040

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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:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cell.2020.10.004DOIArticle
http://dx.doi.org/10.17632/zg7wp4xd5v.1DOIData
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543886PubMed CentralArticle
ORCID:
AuthorORCID
Bhat, Prashant0000-0003-3832-4871
Ollikainen, Noah0000-0002-1174-2400
Voorhees, Rebecca0000-0003-1640-2293
Guttman, Mitchell0000-0003-4748-9352
Additional Information:© 2020 Published by Elsevier. Received 18 June 2020, Revised 26 August 2020, Accepted 2 October 2020, Available online 8 October 2020. We thank Fritz Roth for clones; Marko Jovanovic, Bil Clemons, Shu-ou Shan, and Jamie Wangen for guidance and discussions; Joanna Jachowicz for analyses; Shawna Hiley for editing; Inna-Marie Strazhnik for figures; and Scott Tighe, Pheobe Laaguiby, Roxana del Rio-Guerra, Joyce Oetjen, Philip Eisenhauer, Arvind H. Patel, and Arthur Wickenhagen for technical help. 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. Data and Code Availability: All datasets generated during this study are available at NCBI Short Read Archive: Bioproject PRJNA665692 (viral protein purifications) and PRJNA665581 (nascent and total RNA-Seq). Table S1 is available at Mendeley data archive, Mendeley Data: http://dx.doi.org/10.17632/zg7wp4xd5v.1 Author Contributions: A.K.B. conceived the project and performed protein and 5EU purification, sequencing, NSP1 and 5′ leader flow cytometry, and analyses. M.R.B. developed and optimized viral protein purification methods, optimized and performed translation assays and splicing assays, and led development and execution of biochemical assays and functional experiments. E.A.B. led virus work, designed and performed experiments, and provided guidance and support regarding analyses, ideas, and discussions of the paper. D.D.H. performed NSP1 translational assays and imaging experiments. L.M.C. performed 5′ leader experiments. A.C. performed membrane reporter and puromycin experiments. P.B. developed 5EU selection and splicing analyses. N.O., S.A.Q., A.E.L., R.V., and M.G. performed analyses. D.G.S., D.G., G.D.L., and S.J.R. generated viral antibodies and performed viral infection. C.L. performed imaging and analysis. J.T., Z.D.M., and M.M.S. performed experiments. R.M.V. provided guidance regarding ribosome and SRP structure and function. J.W.B. provided guidance and reagents for virus work. D.M. and M.G. led the project, supervised experiments and analyses, and wrote the paper. Declaration of Interests: The authors declare no competing interests.
Group:Heritage Medical Research Institute
Funders:
Funding AgencyGrant Number
NIH Postdoctoral FellowshipF30HL136080
NIHP20GM125498
NIHP30GM118228-04
NIHGM7616-40
NIH Postdoctoral FellowshipF30CA247447
NIHUM1HL120877
NIHU54GM115516
NIHR41AI132047
NIHU01AI1141997
NIHU01 DA040612
NIHU01 HL130007
USC MD/PhD ProgramUNSPECIFIED
UCLA-Caltech Medical Scientist Training ProgramUNSPECIFIED
American Cancer SocietyPF-17-240-01
Wellcome Trust201366/Z/16/Z
University of VermontUNSPECIFIED
Heritage Medical Research InstituteUNSPECIFIED
New York Stem Cell FoundationUNSPECIFIED
Chan Zuckerberg InitiativeUNSPECIFIED
CaltechUNSPECIFIED
Issue or Number:5
PubMed Central ID:PMC7543886
Record Number:CaltechAUTHORS:20201008-083809040
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20201008-083809040
Official Citation:Abhik K. Banerjee, Mario R. Blanco, Emily A. Bruce, Drew D. Honson, Linlin M. Chen, Amy Chow, Prashant Bhat, Noah Ollikainen, Sofia A. Quinodoz, Colin Loney, Jasmine Thai, Zachary D. Miller, Aaron E. Lin, Madaline M. Schmidt, Douglas G. Stewart, Daniel Goldfarb, Giuditta De Lorenzo, Suzannah J. Rihn, Rebecca M. Voorhees, Jason W. Botten, Devdoot Majumdar, Mitchell Guttman, SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses, Cell, Volume 183, Issue 5, 2020, Pages 1325-1339.e21, ISSN 0092-8674, https://doi.org/10.1016/j.cell.2020.10.004. (http://www.sciencedirect.com/science/article/pii/S0092867420313106)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:105913
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:08 Oct 2020 16:15
Last Modified:25 Nov 2020 21:02

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