SARS-CoV-2 Spike Protein Induces Time-Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres.
SARS‐CoV‐2
cathepsin L
cathepsins
lysosomes
spike protein
Journal
Journal of cellular biochemistry
ISSN: 1097-4644
Titre abrégé: J Cell Biochem
Pays: United States
ID NLM: 8205768
Informations de publication
Date de publication:
07 Jul 2024
07 Jul 2024
Historique:
revised:
11
06
2024
received:
27
03
2024
accepted:
20
06
2024
medline:
7
7
2024
pubmed:
7
7
2024
entrez:
7
7
2024
Statut:
aheadofprint
Résumé
Autophagy and lysosomal pathways are involved in the cell entry of SARS-CoV-2 virus. To infect the host cell, the spike protein of SARS-CoV-2 binds to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). To allow the fusion of the viral envelope with the host cell membrane, the spike protein has to be cleaved. One possible mechanism is the endocytosis of the SARS-CoV-2-ACE2 complex and subsequent cleavage of the spike protein, mainly by the lysosomal protease cathepsin L. However, detailed molecular and dynamic insights into the role of cathepsin L in viral cell entry remain elusive. To address this, HeLa cells and iPSC-derived alveolarspheres were treated with recombinant SARS-CoV-2 spike protein, and the changes in mRNA and protein levels of cathepsins L, B, and D were monitored. Additionally, we studied the effect of cathepsin L deficiency on spike protein internalization and investigated the influence of the spike protein on cathepsin L promoters in vitro. Furthermore, we analyzed variants in the genes coding for cathepsin L, B, D, and ACE2 possibly associated with disease progression using data from Regeneron's COVID Results Browser and our own cohort of 173 patients with COVID-19, exhibiting a variant of ACE2 showing significant association with COVID-19 disease progression. Our in vitro studies revealed a significant increase in cathepsin L mRNA and protein levels following exposure to the SARS-CoV-2 spike protein in HeLa cells, accompanied by elevated mRNA levels of cathepsin B and D in alveolarspheres. Moreover, an increase in cathepsin L promoter activity was detected in vitro upon spike protein treatment. Notably, the knockout of cathepsin L resulted in reduced internalization of the spike protein. The study highlights the importance of cathepsin L and lysosomal proteases in the SARS-CoV-2 spike protein internalization and suggests the potential of lysosomal proteases as possible therapeutic targets against COVID-19 and other viral infections.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e30627Subventions
Organisme : Bayerisches Staatsministerium für Wissenschaft und Kunst
ID : COVID-19 research grant
Organisme : IZKF, Medical Faculty FAU University Erlangen-Nuremberg
ID : N8
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 125440785
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : GRK2162
Organisme : Deutsche Forschungsgemeinschaft (DFG)
ID : 270949263
Informations de copyright
© 2024 The Author(s). Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
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