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bioRxiv · 10.1101/2023.06.13.544745

SARS CoV-2 Envelope protein alters calcium signaling via SERCA interactions

Berta, B.·Tordai, H.·Lukacs, G. L.·Papp, B.·Enyedi, A.·Padanyi, R.·Hegedus, T.
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Abstract

The clinical management of severe COVID-19 cases is not yet well resolved. Therefore, it is important to identify and characterize cell signaling pathways involved in virus pathogenesis that can be targeted therapeutically. Envelope (E) protein is a structural protein of the virus, which is known to be highly expressed in the infected host cell and is a key virulence factor, however, its role is poorly characterized. The E protein is a single-pass transmembrane protein that can assemble into a pentamer forming a viroporin, perturbing Ca2+ homeostasis. Because it is structurally similar to regulins such as, for example, phospholamban, that regulate the sarco/endoplasmic reticulum calcium ATPases (SERCA), we investigated whether the SARS-CoV-2 E protein affects the SERCA system as an exoregulin. Using FRET experiments we demonstrate that E protein can form oligomers with regulins, and thus can alter the monomer/multimer regulin ratio and consequently influence their interactions with SERCAs. We also confirmed that a direct interaction between E protein and SERCA2b results in a decrease in SERCA-mediated ER Ca2+ reload. Structural modeling and molecular dynamics of the complexes indicates an overlapping interaction site for E protein and endogenous regulins. Our results reveal novel links in the host-virus interaction network that play an important role in viral pathogenesis and may provide a new therapeutic target for managing severe inflammatory responses induced by SARS-CoV-2.

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Berta, B., Tordai, H., Lukacs, G. L., Papp, B., Enyedi, A., Padanyi, R., Hegedus, T.. 2023-06-13. SARS CoV-2 Envelope protein alters calcium signaling via SERCA interactions. https://doi.org/10.1101/2023.06.13.544745

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