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

## TL;DR

This study explores how the SARS-CoV-2 spike protein may interfere with a lung sodium channel, potentially contributing to fluid buildup in severe COVID-19.

## Contribution

The paper provides experimental evidence of competitive proteolytic cleavage between SARS-CoV-2 S protein and ENaC.

## Key findings

- Coexpression of SARS-CoV-2 S protein with ENaC reduces channel activity in a cellular model.
- Bidirectional competition for furin-like protease cleavage occurs between ENaC and S protein.
- No significant decrease in gamma ENaC expression was observed in SARS-CoV-2-infected mouse lungs.

## 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 〈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.