The N-terminal domain of SARS-CoV-2 nsp1 plays key roles in suppression of cellular gene expression and preservation of viral gene expression
Aaron S. Mendez,
Michael Ly,
Angélica M. González-Sánchez,
Ella Hartenian,
Nicholas T. Ingolia,
Jamie H. Cate,
Britt A. Glaunsinger
Affiliations
Aaron S. Mendez
Department of Plant & Microbial Biology, University of California, Berkeley, Berkeley, CA, USA
Michael Ly
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Angélica M. González-Sánchez
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; Comparative Biochemistry Graduate Program, University of California, Berkeley, Berkeley, CA, USA
Ella Hartenian
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
Nicholas T. Ingolia
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA
Jamie H. Cate
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA; Molecular Biophysics & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
Britt A. Glaunsinger
Department of Plant & Microbial Biology, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA; California Institute for Quantitative Biosciences, University of California, Berkeley, Berkeley, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA; Howard Hughes Medical Institute, Berkeley, CA, USA; Corresponding author
Summary: Nonstructural protein 1 (nsp1) is a coronavirus (CoV) virulence factor that restricts cellular gene expression by inhibiting translation through blocking the mRNA entry channel of the 40S ribosomal subunit and by promoting mRNA degradation. We perform a detailed structure-guided mutational analysis of severe acute respiratory syndrome (SARS)-CoV-2 nsp1, revealing insights into how it coordinates these activities against host but not viral mRNA. We find that residues in the N-terminal and central regions of nsp1 not involved in docking into the 40S mRNA entry channel nonetheless stabilize its association with the ribosome and mRNA, both enhancing its restriction of host gene expression and enabling mRNA containing the SARS-CoV-2 leader sequence to escape translational repression. These data support a model in which viral mRNA binding functionally alters the association of nsp1 with the ribosome, which has implications for drug targeting and understanding how engineered or emerging mutations in SARS-CoV-2 nsp1 could attenuate the virus.
