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

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

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

2024
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Overview
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.sup.+ channel, ENaC, expressed in type II pneumocytes. Reduced transepithelial Na.sup.+ 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 [alpha]ENaC by furin-like proteases is essential for channel activity. Thus, competition between S protein and [alpha]ENaC 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.