Summary The pandemic coronavirus SARS-CoV-2 threatens public health worldwide. The viral spike protein mediates SARS-CoV-2 entry into host cells and harbors a S1/S2 cleavage site containing multiple arginine residues (multibasic) not found in closely related animal coronaviruses. However, the role of this multibasic cleavage site in SARS-CoV-2 infection is unknown. Here, we report that the cellular protease furin cleaves the spike protein at the S1/S2 site and that cleavage is essential for S-protein-mediated cell-cell fusion and entry into human lung cells. Moreover, optimizing the S1/S2 site increased cell-cell, but not virus-cell, fusion, suggesting that the corresponding viral variants might exhibit increased cell-cell spread and potentially altered virulence. Our results suggest that acquisition of a S1/S2 multibasic cleavage site was essential for SARS-CoV-2 infection of humans and identify furin as a potential target for therapeutic intervention. Graphical Abstract Highlights • The spike protein of SARS-CoV-2 harbors a multibasic S1/S2 site • The host cell protease furin cleaves the SARS-CoV-2 spike protein at the S1/S2 site • Cleavage at the S1/S2 site is essential for spike-driven viral entry into lung cells Coronavirus spike proteins are activated by host cell proteases. Hoffmann and colleagues show that the pandemic SARS-CoV-2 harbors a highly cleavable S1/S2 cleavage site not found in closely related coronaviruses. Cleavage at this site is mediated by furin and is required for viral entry into human lung cells.
【저자키워드】 COVID-19, SARS-CoV-2, TMPRSS2, furin, spike, cleavage, membrane fusion, Entry, S1/S2,