SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses

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

doi:10.1016/j.cell.2020.10.004

SARS-CoV-2 Disrupts Splicing, Translation, and Protein Trafficking to Suppress Host Defenses

Cell. 2020 Nov 25;183(5):1325-1339.e21. doi: 10.1016/j.cell.2020.10.004. Epub 2020 Oct 8.

Authors

Abhik K Banerjee¹, Mario R Blanco², Emily A Bruce³, Drew D Honson², Linlin M Chen², Amy Chow², Prashant Bhat⁴, Noah Ollikainen², Sofia A Quinodoz², Colin Loney⁵, Jasmine Thai², Zachary D Miller⁶, Aaron E Lin⁷, Madaline M Schmidt³, Douglas G Stewart⁵, Daniel Goldfarb⁵, Giuditta De Lorenzo⁵, Suzannah J Rihn⁵, Rebecca M Voorhees², Jason W Botten³, Devdoot Majumdar⁸, Mitchell Guttman⁹

Affiliations

¹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
² Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
³ Departments of Medicine, Division of Immunobiology and Microbiology, and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA.
⁴ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA; David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ MRC-University of Glasgow Centre for Virus Research (CVR), Glasgow G61 1QH, UK.
⁶ Department of Surgery and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Surgery and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Avenue, Burlington, VT 05405, USA. Electronic address: [email protected].
⁹ Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. Electronic address: [email protected].

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.

Keywords: NSP1; NSP16; NSP8; NSP9; RNA-protein interactions; SARS-CoV-2; interferon; mRNA splicing; protein trafficking; translation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
COVID-19 / metabolism*
COVID-19 / virology
Chlorocebus aethiops
HEK293 Cells
Host-Pathogen Interactions*
Humans
Interferons / metabolism
Protein Biosynthesis*
Protein Transport
RNA Splicing*
RNA, Messenger / metabolism
RNA, Ribosomal, 18S / metabolism
RNA, Small Cytoplasmic / chemistry
RNA, Small Cytoplasmic / metabolism
SARS-CoV-2 / metabolism*
Signal Recognition Particle / chemistry
Signal Recognition Particle / metabolism
Vero Cells
Viral Nonstructural Proteins / chemistry
Viral Nonstructural Proteins / metabolism*

Substances

7SL RNA
RNA, Messenger
RNA, Ribosomal, 18S
RNA, Small Cytoplasmic
Signal Recognition Particle
Viral Nonstructural Proteins
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding