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The SARS-CoV-2 spike protein binds and modulates estrogen receptors
Solis, Oscar Beccari, Andrea R. Iaconis, Daniela Talarico, Carmine Ruiz-Bedoya, Camilo A. Nwachukwu, Jerome C. Castelli, Vanessa Bertini, Riccardo Montopoli, Monica
Solis, Oscar
Beccari, Andrea R.
Iaconis, Daniela
Talarico, Carmine
Ruiz-Bedoya, Camilo A.
Nwachukwu, Jerome C.
Castelli, Vanessa
Bertini, Riccardo
Montopoli, Monica
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Pre-print
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2022-05-23
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Biology
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https://doi.org/10.1101/2022.05.21.492920
Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 (ACE2) at the cell surface, which constitutes the primary mechanism driving SARS-CoV-2 infection. Molecular interactions between the transduced S and endogenous proteins likely occur post-infection, but such interactions are not well understood. We used an unbiased primary screen to profile the binding of full-length S against >9,000 human proteins and found significant S-host protein interactions, including one between S and human estrogen receptor alpha (ERα). After confirming this interaction in a secondary assay, we used bioinformatics, supercomputing, and experimental assays to identify a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit and an S-ERα binding mode. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects and ACE2 expression. Noninvasive multimodal PET/CT imaging in SARS-CoV-2-infected hamsters using [18F]fluoroestradiol (FES) localized lung pathology with increased ERα lung levels. Postmortem experiments in lung tissues from SARS-CoV-2-infected hamsters and humans confirmed an increase in cytoplasmic ERα expression and its colocalization with S protein in alveolar macrophages. These findings describe the discovery and characterization of a novel S-ERα interaction, imply a role for S as an NRC, and are poised to advance knowledge of SARS-CoV-2 biology, COVID-19 pathology, and mechanisms of sex differences in the pathology of infectious disease.
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