The Sec61-EMC complex promotes biosynthesis of the SARS-CoV-2 non-structural proteins

The genomic RNA of SARS-CoV-2, the virus responsible for the global COVID-19 pandemic, encodes polyproteins pp1a and pp1ab which contain 16 non-structural proteins (NSPs) that support critical steps in viral replication and infection. Despite this, how the polyproteins are synthesized and inserted into membrane in the host cell remains poorly understood. Here we demonstrate that SARS-CoV-2 exploits the Sec61-endoplasmic reticulum (ER) membrane complex (EMC) translation machinery to promote biosynthesis of the virus polyproteins, leading to successful viral genome replication and infection. The Sec61-EMC complex engages NSP3—the first transmembrane (TM) protein in pp1a/pp1ab—during active translation. Strikingly, of the four TM segments in NSP3, a marginally hydrophobic domain between TM3 and TM4 is required for EMC-binding and confers EMC-dependent expression. Our results reveal an ER-dependent mechanism for translation of the SARS-CoV-2 NSPs during virus infection, offering mechanistic insights and potential targets for new anti-SARS-Cov-2 therapeutic development.