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

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 ...

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human estrogen receptor ? (ER?). 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 ER? cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ER? lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ER? and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ER? interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology.

Date: Dec. 02, 2022

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