Published on Wed Jun 16 2021

SARS-CoV-2 envelope-protein corruption of homeostatic signaling mechanisms in mammalian cells

Schulze, T., Hartel, A., Hoeler, S., Hemming, C., Lehn, R., Tandl, D., Greiner, T., Bertl, A., Shepard, K., Moroni, A., Thiel, G., Rauh, O.

Ep-CoV2 is partially inserted into the membrane of nascent viral particles and into cellular membranes. We found that wild-type Ep- CoV2 corrupted some of the most important homeostatic mechanisms in cells. The data presented here suggest that specific channel function inhibitors of Ep- coV2 can provide cell protection and virostatic

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Abstract

During a SARS-CoV2 infection, host cells produce large amounts of the viral envelope protein (Ep-CoV2). Ep-CoV2 is partially inserted into the membrane of nascent viral particles and into cellular membranes. To mimic the pathophysiological impact of the cellular protein fraction, Ep-CoV2 was overexpressed in mammalian cells and effects on key signaling parameters were monitored. By tagging with green fluorescent protein (GFP), we found that Ep-CoV2 protein is mostly present in the endoplasmic reticulum with additional trace amounts in the plasma membrane. We observed that wild-type Ep-CoV2 and, to a lesser extent, its mutants (N15A, V25F) corrupted some of the most important homeostatic mechanisms in cells. The same was observed with isolated transmembrane domains of the protein. The Ep-CoV2-evoked elevation of intracellular Ca2+ and pH as well as the induced membrane depolarization produced by the presence of the protein interfere with major signal transduction cascades in host cells. These functions of Ep-CoV2, which likely contribute to the pathogenesis of the viral protein, result from the ion-channel activity of the viral protein. Two independent assays, a functional reconstitution of Ep-CoV2 protein in artificial membranes and a rescue of K+-deficient yeast mutants, confirm that Ep-CoV2 generates a cation-conducting channel with a low unitary conductance and a complex ion selectivity. The data presented here suggest that specific channel function inhibitors of Ep-CoV2 can provide cell protection and virostatic effects.