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

Oscar Solis; Andrea R. Beccari; Daniela Iaconis; Carmine Talarico; Camilo A. Ruiz-Bedoya; Jerome C. Nwachukwu; Annamaria Cimini; Vanessa Castelli; Riccardo Bertini; Monica Montopoli; Veronica Cocetta; Stefano Borocci; Ingrid G. Prandi; Kelly Flavahan; Melissa Bahr; Anna Napiorkowski; Giovanni Chillemi; Masato Ooka; Xiaoping Yang; Shiliang Zhang; Menghang Xia; Wei Zheng; Jordi Bonaventura; Martin G. Pomper; Jody E. Hooper; Marisela Morales; Avi Z. Rosenberg; Kendall W. Nettles; Sanjay K. Jain; Marcello Allegretti; Michael Michaelides

doi:10.1126/sciadv.add4150

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

Oscar Solis, Andrea R. Beccari, Daniela Iaconis, Carmine Talarico, Camilo A. Ruiz-Bedoya, Jerome C. Nwachukwu, Annamaria Cimini, Vanessa Castelli, Riccardo Bertini, Monica Montopoli, Veronica Cocetta, Stefano Borocci, Ingrid G. Prandi, Kelly Flavahan, Melissa Bahr, Anna Napiorkowski, Giovanni Chillemi, Masato Ooka, Xiaoping Yang, Shiliang ZhangMenghang Xia, Wei Zheng, Jordi Bonaventura, Martin G. Pomper, Jody E. Hooper, Marisela Morales, Avi Z. Rosenberg, Kendall W. Nettles, Sanjay K. Jain, Marcello Allegretti, Michael Michaelides

School of Medicine

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	eadd4150
Journal	Science Advances
Volume	8
Issue number	48
DOIs	https://doi.org/10.1126/sciadv.add4150
State	Published - Dec 2022

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Solis, O., Beccari, A. R., Iaconis, D., Talarico, C., Ruiz-Bedoya, C. A., Nwachukwu, J. C., Cimini, A., Castelli, V., Bertini, R., Montopoli, M., Cocetta, V., Borocci, S., Prandi, I. G., Flavahan, K., Bahr, M., Napiorkowski, A., Chillemi, G., Ooka, M., Yang, X., ... Michaelides, M. (2022). The SARS-CoV-2 spike protein binds and modulates estrogen receptors. Science Advances, 8(48), Article eadd4150. https://doi.org/10.1126/sciadv.add4150

Solis, O, Beccari, AR, Iaconis, D, Talarico, C, Ruiz-Bedoya, CA, Nwachukwu, JC, Cimini, A, Castelli, V, Bertini, R, Montopoli, M, Cocetta, V, Borocci, S, Prandi, IG, Flavahan, K, Bahr, M, Napiorkowski, A, Chillemi, G, Ooka, M, Yang, X, Zhang, S, Xia, M, Zheng, W, Bonaventura, J, Pomper, MG, Hooper, JE, Morales, M, Rosenberg, AZ, Nettles, KW, Jain, SK, Allegretti, M & Michaelides, M 2022, 'The SARS-CoV-2 spike protein binds and modulates estrogen receptors', Science Advances, vol. 8, no. 48, eadd4150. https://doi.org/10.1126/sciadv.add4150

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title = "The SARS-CoV-2 spike protein binds and modulates estrogen receptors",

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.",

author = "Oscar Solis and Beccari, {Andrea R.} and Daniela Iaconis and Carmine Talarico and Ruiz-Bedoya, {Camilo A.} and Nwachukwu, {Jerome C.} and Annamaria Cimini and Vanessa Castelli and Riccardo Bertini and Monica Montopoli and Veronica Cocetta and Stefano Borocci and Prandi, {Ingrid G.} 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 Pomper, {Martin G.} and Hooper, {Jody E.} and Marisela Morales and Rosenberg, {Avi Z.} and Nettles, {Kendall W.} and Jain, {Sanjay K.} and Marcello Allegretti and Michael Michaelides",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors.",

year = "2022",

month = dec,

doi = "10.1126/sciadv.add4150",

language = "English (US)",

volume = "8",

journal = "Science Advances",

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AU - Solis, Oscar

AU - Beccari, Andrea R.

AU - Iaconis, Daniela

AU - Talarico, Carmine

AU - Ruiz-Bedoya, Camilo A.

AU - Nwachukwu, Jerome C.

AU - Cimini, Annamaria

AU - Castelli, Vanessa

AU - Bertini, Riccardo

AU - Montopoli, Monica

AU - Cocetta, Veronica

AU - Borocci, Stefano

AU - Prandi, Ingrid G.

AU - Flavahan, Kelly

AU - Bahr, Melissa

AU - Napiorkowski, Anna

AU - Chillemi, Giovanni

AU - Ooka, Masato

AU - Yang, Xiaoping

AU - Zhang, Shiliang

AU - Xia, Menghang

AU - Zheng, Wei

AU - Bonaventura, Jordi

AU - Pomper, Martin G.

AU - Hooper, Jody E.

AU - Morales, Marisela

AU - Rosenberg, Avi Z.

AU - Nettles, Kendall W.

AU - Jain, Sanjay K.

AU - Allegretti, Marcello

AU - Michaelides, Michael

PY - 2022/12

Y1 - 2022/12

N2 - 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.

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

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