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    The SARS-CoV-2 spike protein binds and modulates estrogen receptors

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    Cimini-PrePrint-2022.pdf
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    Genre
    Pre-print
    Date
    2022-05-23
    Author
    Solis, Oscar
    Beccari, Andrea R.
    Iaconis, Daniela
    Talarico, Carmine
    Ruiz-Bedoya, Camilo A.
    Nwachukwu, Jerome C.
    Cimini, Annamaria cc
    Castelli, Vanessa
    Bertini, Riccardo
    Montopoli, Monica
    Cocetta, Veronica
    Borocci, Stefano
    Prandi, Ingrid G.
    Flavahan, Kelly
    Bahr, Melissa
    Napiorkowski, Anna
    Chillemi, Giovanni
    Ooka, Masato
    Yang, Xiaoping
    Zhang, Shiliang
    Xia, Menghang
    Zheng, Wei
    Bonaventura, Jordi
    Pomper, Jody E.
    Morales, Marisela
    Rosenberg, Avi Z.
    Nettles, Kendall W.
    Jain, Sanjay K.
    Allegretti, Marcello
    Michaelides, Michael
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    Department
    Biology
    Subject
    Immunology
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/8086; http://dx.doi.org/10.34944/dspace/8058
    
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    DOI
    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.
    Citation to related work
    bioRxiv
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    http://dx.doi.org/10.34944/dspace/8058
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