Different host cell proteases activate the SARS-coronavirus spike-protein for cell-cell and virus-cell fusion |
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Authors: | Simmons Graham Bertram Stephanie Glowacka Ilona Steffen Imke Chaipan Chawaree Agudelo Juliet Lu Kai Rennekamp Andrew J Hofmann Heike Bates Paul Pöhlmann Stefan |
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Institution: | a Blood Systems Research Institute and Department of Laboratory Medicine, University of California, San Francisco, CA, USAb Institute of Virology, Hannover Medical School, 30625 Hannover, Germanyc Institute for Virology, University Hospital Erlangen, 91054 Erlangen, Germanyd Nikolaus-Fiebiger-Center, University Hospital Erlangen, 91054 Erlangen, Germanye Department of Microbiology, University of Pennsylvania, PA 19104-6076, USAf Department of Medical Microbiology and Virology, University of Kiel, 24105 Kiel, Germanyg German Primate Center, Infection Biology Unit, 37077 Göttingen, Germany |
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Abstract: | Severe acute respiratory syndrome coronavirus (SARS-CoV) poses a considerable threat to human health. Activation of the viral spike (S)-protein by host cell proteases is essential for viral infectivity. However, the cleavage sites in SARS-S and the protease(s) activating SARS-S are incompletely defined. We found that R667 was dispensable for SARS-S-driven virus-cell fusion and for SARS-S-activation by trypsin and cathepsin L in a virus-virus fusion assay. Mutation T760R, which optimizes the minimal furin consensus motif 758-RXXR-762, and furin overexpression augmented SARS-S activity, but did not result in detectable SARS-S cleavage. Finally, SARS-S-driven cell-cell fusion was independent of cathepsin L, a protease essential for virus-cell fusion. Instead, a so far unknown leupeptin-sensitive host cell protease activated cellular SARS-S for fusion with target cells expressing high levels of ACE2. Thus, different host cell proteases activate SARS-S for virus-cell and cell-cell fusion and SARS-S cleavage at R667 and 758-RXXR-762 can be dispensable for SARS-S activation. |
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Keywords: | SARS coronavirus Spike protein Proteolytic cleavage Cathepsin L Furin |
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