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

Oscar Solís, Ph.D.

Oscar Solís, Ph.D.

Featured Paper of the Month – April 2023

Published in Science Advances by Oscar Solís and Michael Michaelides et al. from the NIDA IRP Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit.

Summary

In our study, we investigated the potential impact of the spike protein of the SARS-CoV-2 virus on estrogen receptors. To do so, we used computational and biochemical methods to study the binding of the spike protein to human estrogen receptors. Our findings suggest that the spike protein has a high affinity for estrogen receptors and can bind to them, potentially altering their function. We show that the spike protein may interfere with the normal signaling of estrogen receptors, which could have implications for estrogen-dependent processes. Interestingly, our study suggests that the interaction between the spike protein and estrogen receptors may explain some of the sex-based differences in COVID-19. It is important to note that our study has limitations and further research is needed to confirm the findings and explore the implications of this interaction for COVID-19 and other diseases. Nevertheless, our findings may have implications for the development of treatments and vaccines for COVID-19 that target the spike protein.

Publication Information

Solis, Oscar; Beccari, 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, Martin G; Hooper, Jody E; Morales, Marisela; Rosenberg, Avi Z; Nettles, Kendall W; Jain, Sanjay K; Allegretti, Marcello; Michaelides, Michael

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

In: Sci Adv, vol. 8, no. 48, pp. eadd4150, 2022, ISSN: 2375-2548.

Abstract | Links

@article{pmid36449624,
title = {The SARS-CoV-2 spike protein binds and modulates estrogen receptors},
author = {Oscar Solis and Andrea R Beccari and Daniela Iaconis and Carmine Talarico and Camilo A Ruiz-Bedoya and Jerome C Nwachukwu and Annamaria Cimini and Vanessa Castelli and Riccardo Bertini and Monica Montopoli and Veronica Cocetta and Stefano Borocci and Ingrid G Prandi and Kelly Flavahan and Melissa Bahr and Anna Napiorkowski and Giovanni Chillemi and Masato Ooka and Xiaoping Yang and Shiliang Zhang and Menghang Xia and Wei Zheng and Jordi Bonaventura and Martin G Pomper and Jody E Hooper and Marisela Morales and Avi Z Rosenberg and Kendall W Nettles and Sanjay K Jain and Marcello Allegretti and Michael Michaelides},
url = {https://pubmed.ncbi.nlm.nih.gov/36449624/},
doi = {10.1126/sciadv.add4150},
issn = {2375-2548},
year = {2022},
date = {2022-12-01},
urldate = {2022-12-01},
journal = {Sci Adv},
volume = {8},
number = {48},
pages = {eadd4150},
abstract = {The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor α (ERα). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ERα lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ERα and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ERα interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor α (ERα). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ERα lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ERα and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ERα interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology.

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  • https://pubmed.ncbi.nlm.nih.gov/36449624/
  • doi:10.1126/sciadv.add4150

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