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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\u2010CoV\u20102\u2013ACE2 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\u2010derived alveolarspheres were treated with recombinant SARS\u2010CoV\u20102 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\u201019, exhibiting a variant of <jats:italic>ACE2<\/jats:italic> showing significant association with COVID\u201019 disease progression. Our in vitro studies revealed a significant increase in cathepsin L mRNA and protein levels following exposure to the SARS\u2010CoV\u20102 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\u2010CoV\u20102 spike protein internalization and suggests the potential of lysosomal proteases as possible therapeutic targets against COVID\u201019 and other viral infections.<\/jats:p>","DOI":"10.1002\/jcb.30627","type":"journal-article","created":{"date-parts":[[2024,7,7]],"date-time":"2024-07-07T10:09:35Z","timestamp":1720346975000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SARS\u2010CoV\u20102 Spike Protein Induces Time\u2010Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres"],"prefix":"10.1002","volume":"125","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3020-9943","authenticated-orcid":false,"given":"Magdalena M.","family":"Bolsinger","sequence":"first","affiliation":[{"name":"Department of Molecular Neurology, University Hospital Erlangen Friedrich\u2010Alexander\u2010Universit\u00e4t 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