Human coronavirus dependency on host heat shock protein 90 reveals an antiviral target

ABSTRACT

Rapid accumulation of viral proteins in host cells render viruses highly dependent on cellular chaperones including heat shock protein 90 (Hsp90). Three highly pathogenic human coronaviruses, including MERS-CoV, SARS-CoV and SARS-CoV-2, have emerged in the past 2 decades. However, there is no approved antiviral agent against these coronaviruses. We inspected the role of Hsp90 for coronavirus propagation. First, an Hsp90 inhibitor, 17-AAG, significantly suppressed MERS-CoV propagation in cell lines and physiological-relevant human intestinal organoids. Second, siRNA depletion of Hsp90β, but not Hsp90α, significantly restricted MERS-CoV replication and abolished virus spread. Third, Hsp90β interaction with MERS-CoV nucleoprotein (NP) was revealed in a co-immunoprecipitation assay. Hsp90β is required to maintain NP stability. Fourth, 17-AAG substantially inhibited the propagation of SARS-CoV and SARS-CoV-2. Collectively, Hsp90 is a host dependency factor for human coronavirus MERS-CoV, SARS-CoV and SARS-COV-2. Hsp90 inhibitors can be repurposed as a potent and broad-spectrum antiviral against human coronaviruses.

KEYWORDS:

• Coronavirus
• Hsp90β
• SARS-CoV-2
• nucleoprotein
• viral replication

Acknowledgements

We thank the Center of PanorOmic Sciences and Electron Microscope Unit, Li Ka Shing Faculty of Medicine, University of Hong Kong, for assistance in confocal imaging flow cytometry, and electron microscopy.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was partly supported by funding from Health and Medical Research Fund [grant numbers 17161272, 19180392] of the Food and Health Bureau of the Hong Kong Special Administrative Region (HKSAR) to J.Z.; General Research Fund [grant number 17105420] of the Research Grants Council, HKSAR government to J.Z.; Theme-based Research Scheme [grant number T11-707/15-R] of the Research Grants Council, HKSAR Government to K.Y.Y.; the High Level Hospital-Summit Programme in Guangdong, The University of Hong Kong-Shenzhen Hospital to K.Y.Y.; and the donations of the Shaw Foundation Hong Kong, May Tam Mak Mei Yin, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy & Chow Sin Lan Charity Fund Limited, and Chan Yin Chuen Memorial Charitable Foundation to K.Y.Y.