The SARS-CoV-2 spike protein binds and modulates estrogen receptors
Genre
Pre-printDate
2022-05-23Author
Solis, OscarBeccari, Andrea R.
Iaconis, Daniela
Talarico, Carmine
Ruiz-Bedoya, Camilo A.
Nwachukwu, Jerome C.
Cimini, Annamaria

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
Department
BiologySubject
ImmunologyPermanent link to this record
http://hdl.handle.net/20.500.12613/8086; http://dx.doi.org/10.34944/dspace/8058
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https://doi.org/10.1101/2022.05.21.492920Abstract
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
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http://dx.doi.org/10.34944/dspace/8058