Effect of SARS-CoV-2 S protein on the proteolytic cleavage of the epithelial Na+ channel ENaC.

Severe cases of COVID-19 are characterized by development of acute respiratory distress syndrome (ARDS). Water accumulation in the lungs is thought to occur as consequence of an exaggerated inflammatory response. A possible mechanism could involve decreased activity of the epithelial Na+ channel, ENaC, expressed in type II pneumocytes. Reduced transepithelial Na+ reabsorption could contribute to lung edema due to reduced alveolar fluid clearance. This hypothesis is based on the observation of the presence of a novel furin cleavage site in the S protein of SARS-CoV-2 that is identical to the furin cleavage site present in the alpha subunit of ENaC. Proteolytic processing of αENaC by furin-like proteases is essential for channel activity. Thus, competition between S protein and αENaC for furin-mediated cleavage in SARS-CoV-2-infected cells may negatively affect channel activity. Here we present experimental evidence showing that coexpression of the S protein with ENaC in a cellular model reduces channel activity. In addition, we show that bidirectional competition for cleavage by furin-like proteases occurs between 〈ENaC and S protein. In transgenic mice sensitive to lethal SARS-CoV-2, however, a significant decrease in gamma ENaC expression was not observed by immunostaining of lungs infected as shown by SARS-CoV2 nucleoprotein staining.
Competing Interests: During these studies, G. Gamba received unrelated support from the National Institutes of Health (grant DK51496). D. Batlle and J. Wysocki are coinventors of patents entitled “Active low molecular weight variants of angiotensin converting enzyme 2 (ACE2), “Soluble ACE2 variants and uses therefor.” D. Batlle is founder of Angiotensin Theraputics, Inc. D. Batlle has received consulting fees from Advience and Traveri, all unrelated to this work. During these studies, D. Batlle received unrelated support from the National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK104785) and from a grant from AstraZeneca. D. Batlle also reports research funding from the Feinberg Foundation; J. Wysocki reports being a scientific advisor for Angiotensin Therapeutics, Inc. All other authors have nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
(Copyright: © 2024 Magaña-Ávila et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)