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

• Published in: PloS one 2024-04, Vol.19 (4), p.e0302436-e0302436
• Main Authors: Magaña-Ávila, Germán Ricardo, Moreno, Erika, Plata, Consuelo, Carbajal-Contreras, Héctor, Murillo-de-Ozores, Adrian Rafael, García-Ávila, Kevin, Vázquez, Norma, Syed, Maria, Wysocki, Jan, Batlle, Daniel, Gamba, Gerardo, Castañeda-Bueno, María
• Format: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - virology; Animals; Biology and life sciences; COVID-19 - metabolism; COVID-19 - virology; Epithelial Sodium Channels - metabolism; Furin - metabolism; HEK293 Cells; Humans; Lung - metabolism; Lung - pathology; Lung - virology; Medicine and health sciences; Mice; Mice, Transgenic; Proteolysis; Research and Analysis Methods; SARS-CoV-2 - metabolism; SARS-CoV-2 - pathogenicity; Spike Glycoprotein, Coronavirus - metabolism
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0302436

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.