A Transmembrane Serine Protease Is Linked to the Severe Acute Respiratory Syndrome Coronavirus Receptor and Activates Virus Entry

TLDR

Coronaviruses use spike proteins to bind host receptors and fuse with cell membranes, a process that requires proteolytic activation and is facilitated by the receptor angiotensin‑converting enzyme 2 (ACE2). The study hypothesized that proteases closely linked to host cell receptors are key to SARS‑CoV entry. ACE2 was found to associate with the transmembrane serine protease TMPRSS2, and their colocalization on the cell surface increased SARS‑CoV entry through proteolytic cleavage of both spike protein and ACE2, demonstrating that a receptor–protease complex activates viral entry.

Abstract

Spike (S) proteins, the defining projections of the enveloped coronaviruses (CoVs), mediate cell entry by connecting viruses to plasma membrane receptors and by catalyzing subsequent virus-cell membrane fusions. The latter membrane fusion requires an S protein conformational flexibility that is facilitated by proteolytic cleavages. We hypothesized that the most relevant cellular proteases in this process are those closely linked to host cell receptors. The primary receptor for the human severe acute respiratory syndrome CoV (SARS) CoV is angiotensin-converting enzyme 2 (ACE2). ACE2 immunoprecipitation captured transmembrane protease/serine subfamily member 2 (TMPRSS2), a known human airway and alveolar protease. ACE2 and TMPRSS2 colocalized on cell surfaces and enhanced the cell entry of both SARS S-pseudotyped HIV and authentic SARS-CoV. Enhanced entry correlated with TMPRSS2-mediated proteolysis of both S and ACE2. These findings indicate that a cell surface complex comprising a primary receptor and a separate endoprotease operates as a portal for activation of SARS-CoV cell entry.