Tweet
Published: September 19, 2023
DOI:https://doi.org/10.1016/j.celrep.2023.113156
Swapnil C. Devarkar 5, Michael Vetick 5, Shravani Balaji, Wendy V. Gilbert, Sidi Chen, Yong Xiong 6, Show all authors
Highlights
All betacoronaviruses (β-CoVs) encode non-structural protein 1 (Nsp1), an essential pathogenicity factor that potently restricts host gene expression. Among the β-CoV family, MERS-CoV is the most distantly related member to SARS-CoV-2, and the mechanism for host translation inhibition by MERS-CoV Nsp1 remains controversial. Herein, we show that MERS-CoV Nsp1 directly interacts with the 40S ribosomal subunit. Using cryogenic electron microscopy (cryo-EM), we report a 2.6-Å structure of the MERS-CoV Nsp1 bound to the human 40S ribosomal subunit. The extensive interactions between C-terminal domain of MERS-CoV Nsp1 and the mRNA entry channel of the 40S ribosomal subunit are critical for its translation inhibition function. This mechanism of MERS-CoV Nsp1 is strikingly similar to SARS-CoV and SARS-CoV-2 Nsp1, despite modest sequence conservation. Our results reveal that the mechanism of host translation inhibition is conserved across β-CoVs and highlight a potential therapeutic target for the development of antivirals that broadly restrict β-CoVs.
Graphical abstract
DOI:https://doi.org/10.1016/j.celrep.2023.113156
Swapnil C. Devarkar 5, Michael Vetick 5, Shravani Balaji, Wendy V. Gilbert, Sidi Chen, Yong Xiong 6, Show all authors
Highlights
- •
MERS-CoV Nsp1 directly interacts with the human 40S ribosome and inhibits translation - •
The CTD of MERS-CoV Nsp1 sterically blocks the mRNA entry channel of the 40S ribosome - •
CTD of MERS-CoV Nsp1 is indispensable for its translation inhibition activity - •
Evolutionarily divergent SARS-CoV-2 and MERS-CoV Nsp1 share a remarkably conserved mechanism
All betacoronaviruses (β-CoVs) encode non-structural protein 1 (Nsp1), an essential pathogenicity factor that potently restricts host gene expression. Among the β-CoV family, MERS-CoV is the most distantly related member to SARS-CoV-2, and the mechanism for host translation inhibition by MERS-CoV Nsp1 remains controversial. Herein, we show that MERS-CoV Nsp1 directly interacts with the 40S ribosomal subunit. Using cryogenic electron microscopy (cryo-EM), we report a 2.6-Å structure of the MERS-CoV Nsp1 bound to the human 40S ribosomal subunit. The extensive interactions between C-terminal domain of MERS-CoV Nsp1 and the mRNA entry channel of the 40S ribosomal subunit are critical for its translation inhibition function. This mechanism of MERS-CoV Nsp1 is strikingly similar to SARS-CoV and SARS-CoV-2 Nsp1, despite modest sequence conservation. Our results reveal that the mechanism of host translation inhibition is conserved across β-CoVs and highlight a potential therapeutic target for the development of antivirals that broadly restrict β-CoVs.
Graphical abstract
