The SARS-CoV-2 spike protein binds and modulates estrogen receptors-Reference-Cited by-同舟云学术

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

Published:2022-12-02 Issue:48 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Solis Oscar¹^ORCID,Beccari Andrea R.²^ORCID,Iaconis Daniela²^ORCID,Talarico Carmine²^ORCID,Ruiz-Bedoya Camilo A.³⁴⁵^ORCID,Nwachukwu Jerome C.⁶^ORCID,Cimini Annamaria⁷⁸,Castelli Vanessa⁷^ORCID,Bertini Riccardo⁹,Montopoli Monica¹⁰¹¹,Cocetta Veronica¹⁰^ORCID,Borocci Stefano¹²,Prandi Ingrid G.¹²^ORCID,Flavahan Kelly³⁴⁵,Bahr Melissa³⁴⁵^ORCID,Napiorkowski Anna³⁴⁵^ORCID,Chillemi Giovanni¹²^ORCID,Ooka Masato¹³^ORCID,Yang Xiaoping¹⁴^ORCID,Zhang Shiliang¹⁵^ORCID,Xia Menghang¹³^ORCID,Zheng Wei¹³^ORCID,Bonaventura Jordi¹⁶^ORCID,Pomper Martin G.¹⁷^ORCID,Hooper Jody E.¹⁸^ORCID,Morales Marisela¹⁵,Rosenberg Avi Z.¹⁴^ORCID,Nettles Kendall W.⁶,Jain Sanjay K.³⁴⁵^ORCID,Allegretti Marcello¹⁹^ORCID,Michaelides Michael¹²⁰^ORCID

Affiliation:

1. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

2. EXSCALATE, Dompé farmaceutici S.p.A, Napoli, Italy.

3. Center for Infection and Inflammation Imaging Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

4. Department of Pediatrics, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB-II Room 109, Baltimore, MD 21287, USA.

5. Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

6. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.

7. Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy.

8. Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA.

9. Atreius S.a.s., L’Aquila, Italy.

10. Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.

11. VIMM- Veneto Institute of Molecular Medicine, Fondazione per la Ricerca Biomedica Avanzata, Padova, Italy.

12. Department for Innovation in Biological, Agro-Food and Forest Systems, DIBAF, University of Tuscia, Viterbo, Italy.

13. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD 20850, USA.

14. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

15. Neuronal Networks Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD 21224, USA.

16. Departament de Patologia i Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L’Hospitalet de Llobregat, Catalonia, Spain.

17. Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

18. Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

19. Dompé farmaceutici S.p.A, L’Aquila, Italy.

20. Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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