📄 Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease

The highly pathogenic severe acute respiratory syndrome coronavirus (SARS-CoV) poses a constant threat to human health. The viral spike protein (SARS-S) mediates host cell entry and is a potential target for antiviral intervention. Activation of SARS-S by host cell proteases is essential for SARS-CoV infectivity but remains incompletely understood. Here, we analyzed the role of the type II transmembrane serine proteases (TTSPs) human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2), in SARS-S activation. We found that HAT activates SARS-S in the context of surrogate systems and authentic SARS-CoV infection and is coexpressed with the viral receptor angiotensin-converting enzyme 2 (ACE2) in bronchial epithelial cells and pneumocytes. HAT cleaved SARS-S at R667, as determined by mutagenesis and mass spectrometry, and activated SARS-S for cell-cell fusion in cis and trans, while the related pulmonary protease TMPRSS2 cleaved SARS-S at multiple sites and activated SARS-S only in trans. However, TMPRSS2 but not HAT expression rendered SARS-S-driven virus-cell fusion independent of cathepsin activity, indicating that HAT and TMPRSS2 activate SARS-S differentially. Collectively, our results show that HAT cleaves and activates SARS-S and might support viral spread in patients. © 2011, American Society for Microbiology.

keywords 🔗 severe acute (1373) 🔗 syndrome coronavirus (1074) 🔗 cell-cell fusion (34) 🔗 receptor angiotensin-converting (14) 🔗 spike protein (353) 🔗 highly pathogenic (100) 🔗 host cell (262) 🔗 mass spectrometry (26) 🔗 converting enzyme (162) 🔗 respiratory syndrome (2004) 🔗 angiotensin-converting enzyme (112) 🔗 acute respiratory (1734) 🔗 epithelial cells (128)

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