The Impact of Coronavirus Nsp1 on Host mRNA Degradation Is Independent of Its Role in Translation Inhibition

Abstract

When host cells are infected with coronaviruses, the first viral protein produced is Nsp1. This protein inhibits host protein synthesis and induces host mRNA degradation to enhance viral proliferation. Despite its critical role, the mechanism by which Nsp1 mediates cellular mRNA degradation remains unclear. In this study, we use cell-free translation to address how the host mRNA stability is regulated by Nsp1. We reveal that SARS-CoV-2 Nsp1 binding to the ribosome is enough to trigger mRNA degradation independently of ribosome collisions or active translation. MERS-CoV Nsp1 inhibits translation without triggering degradation, highlighting mechanistic differences between the two Nsp1 counterparts. Nsp1 and viral mRNAs appear to co-evolve, rendering viral mRNAs immune to Nsp1-mediated degradation in SARS-CoV-2, MERS-CoV and Bat-Hp viruses. By providing new insights into the mode of action of Nsp1, our study helps to understand the biology of Nsp1 better and find new strategies for therapeutic targeting against coronaviral infections. SignificanceO_LICell-free assays allow the decoupling of Nsp1-mediated translation inhibition from RNA degradation. C_LIO_LINsp1 interaction with the ribosome is crucial for mRNA degradation, but active translation is not required. C_LIO_LISARS-CoV-2 Nsp1 induces mRNA degradation, while MERS-CoV Nsp1 inhibits translation without triggering degradation. C_LIO_LI5UTR-specific protection of viral mRNAs from Nsp1 indicates a co-evolutionary adaptation between the two features C_LI