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

Abstract

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 hENaC 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.