SARS-CoV-2 NSP2 specifically interacts with cellular protein SmgGDS

Abstract

The novel coronavirus, SARS-CoV-2, is responsible for the ongoing global pandemic of Coronavirus disease 2019 (COVID-19). SARS-CoV-2 belongs to the Coronaviridae family, which also includes the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Recent studies using affinity purification mass spectrometry analysis have revealed that SARS-CoV-2 NSP2 may interact with cellular protein Small G-protein dissociation stimulator (SmgGDS), a guanine nucleotide exchange factor (GEF) that specifically regulates RhoA and RhoC proteins, which are involved in a range of cellular activities, including actin reorganization, cell motility and adhesion. Biochemical experiments have confirmed that NSP2 binds directly to SmgGDS and that this interaction requires the full-length NSP2. Given the low sequence conservation compared to other coronaviruses, this interaction with SmgGDS appears specific to SARS-CoV-2, with similar proteins in other coronaviruses unable to bind SmgGDS. Further studies have revealed that the binding of SARS-CoV-2 NSP2 to SmgGDS has a significant inhibitory effect on the GEF activity of SmgGDS. This inhibition disrupts the nucleotide exchange process on RhoA, impairing its function and potentially contributing to the pathogenic mechanisms of SARS-CoV-2. These findings highlight a novel pathway through which SARS-CoV-2 may influence host cellular processes, providing insights into the unique impact of coronaviruses on cellular regulation.