SARS-CoV-2 nsp16 is regulated by host E3 ubiquitin ligases, UBR5 and MARCHF7

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), is a global public health threat with a significant economic burden. The non-structural protein 16 (nsp16) of SARS-CoV-2, in complex with nsp10, catalyses the final step of viral mRNA capping via its 2’-O-methylase activity. This function helps the virus evade host immunity and protect viral mRNA from degradation. Current literature has not thoroughly investigated the host factors that regulate nsp16. Although various E3 ubiquitin ligases are known to interact with SARS-CoV-2 proteins, their specific roles in targeting nsp16 for degradation have not been elucidated. Here, we demonstrate that nsp16 is ubiquitinated and degraded by host E3 ubiquitin ligases UBR5 and MARCHF7, acting through the ubiquitin-proteasome system (UPS). UBR5 and MARCHF7 induce nsp16 degradation via K48-and K27-linked ubiquitination, respectively. Moreover, this degradation by either UBR5 or MARCHF7 is independent, and both processes inhibit SARS-CoV-2 replication in vitro as well as in vivo. Further, UBR5 and MARCHF7 exhibited broad-spectrum antiviral potential by degrading nsp16 variants from different SARS-CoV-2 strains. Our findings provide novel insights into the role of the UPS in antagonising SARS-CoV-2 replication and open new avenues for therapeutic interventions against COVID-19.