SARS-CoV-2 uses a multipronged strategy to impede host protein synthesis

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 pandemic¹. Coronaviruses developed varied mechanisms to repress host mRNA translation to allow the translation of viral mRNAs and concomitantly block the cellular innate immune response^2,3. Although different SARS-CoV-2 proteins are implicated in host expression shutoff^4–7, a comprehensive picture of the effects of SARS-CoV-2 infection on cellular gene expression is lacking. Here, we combine RNA-sequencing, ribosome profiling and metabolic labeling of newly synthesized RNA, to comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis. We show that infection leads to a global reduction in translation, but viral transcripts are not preferentially translated. Instead, we find that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells. Moreover, we reveal that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired. We demonstrate this impairment is likely mediated by inhibition of nuclear mRNA export, preventing newly transcribed cellular mRNAs from accessing ribosomes. Overall, our results uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.