The SARS-CoV-2 spike protein binds and modulates estrogen receptors
Óscar Solís, Andrea R. Beccari, Daniela Iaconis, Carmine Talarico, Camilo A. Ruiz-Bedoya, J.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, K.W. Nettles, Sanjay K. Jain, Marcello Allegretti, Michael Michaelides
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.