Identification of SARS-CoV-2 proteins suppressing host protein synthesis.

Viruses hijack cellular resources in order to produce large quantities of progenies in a short period of time. One viral strategy to achieve this goal is to shut off host gene expression, including cellular protein synthesis. To gain insights into the host shutoff mechanism employed by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we determined which of its viral proteins have the capacity to inhibit the synthesis of nascent host proteins. Our results revealed that, in addition to the non-structural protein NSP1, well-documented for inhibiting translation by binding to the mRNA entry channel in the 40S ribosomal subunit, viral proteins NSP5, NSP13 and NSP15 also markedly suppress host protein synthesis. Further experiments showed that the enzymatic activities of these three latter viral proteins are required for translation inhibition, and that NSP1, NSP5 and NSP13 markedly diminish the formation of polysomes, suggesting a mechanism of disrupting the initiation stage of translation. Interestingly, no stress granule formation was detected in cells expressing these translation inhibitory viral proteins. Together, our data support a multi-pronged strategy SARS-CoV-2 uses to achieve optimal shutoff of host gene expression.