TY - JOUR
T1 - Effect of SARS-CoV-2 S protein on the proteolytic cleavage of the epithelial Na+ channel ENaC
AU - Magaña-Ávila, Germán Ricardo
AU - Moreno, Erika
AU - Plata, Consuelo
AU - Carbajal-Contreras, Héctor
AU - Murillo-De-Ozores, Adrian Rafael
AU - García-Ávila, Kevin
AU - Vázquez, Norma
AU - Syed, Maria
AU - Wysocki, Jan
AU - Batlle, Daniel
AU - Gamba, Gerardo
AU - Castañeda-Bueno, María
N1 - Publisher 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.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85191512369&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85191512369&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0302436
DO - 10.1371/journal.pone.0302436
M3 - Article
C2 - 38662786
AN - SCOPUS:85191512369
SN - 1932-6203
VL - 19
JO - PloS one
JF - PloS one
IS - 4 April
M1 - e0302436
ER -