A transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry.
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.
Department of Microbiology and Immunology, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA.
Ana
A
Shulla
Taylor
T
Heald-Sargent
Gitanjali
G
Subramanya
Jincun
J
Zhao
Stanley
S
Perlman
Tom
T
Gallagher
D000085962:Angiotensin-Converting Enzyme 2; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D006801:Humans; D047468:Immunoprecipitation; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D045473:Severe acute respiratory syndrome-related coronavirus / Q000502:physiology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D053586:Virus Internalization
D011991:Receptors, Virus; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; D000085962:Angiotensin-Converting Enzyme 2; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human