tetano
Editor, Senior Moderator
PLoS One
. 2025 Aug 14;20(8):e0328879.
doi: 10.1371/journal.pone.0328879. eCollection 2025. Amino acid residues 655 and 969 in the spike protein of Omicron subvariant BA.1 control use of TMPRSS2 versus Cathepsin L dependent entry pathways and cell tropism
Cheila Rocha[SUP] 1 2 [/SUP], Prerna Arora[SUP] 1 2 [/SUP], Lu Zhang[SUP] 1 2 [/SUP], Anzhalika Sidarovich[SUP] 1 2 [/SUP], Luise Graichen[SUP] 1 2 [/SUP], Anna-Sophie Moldenhauer[SUP] 1 [/SUP], Stefan Pöhlmann[SUP] 1 2 [/SUP], Markus Hoffmann[SUP] 1 [/SUP]
Affiliations
The spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is activated by the host cell proteases cathepsin L or TMPRSS2. The ancestral virus circulating in Wuhan in 2020 and early variants mainly use TMPRSS2 for entry into Calu-3 lung cells while the Omicron subvariant BA.1 and most subsequently circulating Omicron subvariants employ both cathepsin L and TMPRSS2 for Calu-3 cell entry. Here, we investigated which amino acid residues in the S protein of the Omicron subvariant BA.1 control protease choice. We show that Y655 promotes S protein cleavage and cathepsin L-dependent entry while H655 jointly with N969 promotes TMPRSS2-dependent entry. These results define molecular signatures of SARS-CoV-2 protease choice and lung cell infection.
. 2025 Aug 14;20(8):e0328879.
doi: 10.1371/journal.pone.0328879. eCollection 2025. Amino acid residues 655 and 969 in the spike protein of Omicron subvariant BA.1 control use of TMPRSS2 versus Cathepsin L dependent entry pathways and cell tropism
Cheila Rocha[SUP] 1 2 [/SUP], Prerna Arora[SUP] 1 2 [/SUP], Lu Zhang[SUP] 1 2 [/SUP], Anzhalika Sidarovich[SUP] 1 2 [/SUP], Luise Graichen[SUP] 1 2 [/SUP], Anna-Sophie Moldenhauer[SUP] 1 [/SUP], Stefan Pöhlmann[SUP] 1 2 [/SUP], Markus Hoffmann[SUP] 1 [/SUP]
Affiliations
- PMID: 40811574
- PMCID: PMC12352760
- DOI: 10.1371/journal.pone.0328879
The spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is activated by the host cell proteases cathepsin L or TMPRSS2. The ancestral virus circulating in Wuhan in 2020 and early variants mainly use TMPRSS2 for entry into Calu-3 lung cells while the Omicron subvariant BA.1 and most subsequently circulating Omicron subvariants employ both cathepsin L and TMPRSS2 for Calu-3 cell entry. Here, we investigated which amino acid residues in the S protein of the Omicron subvariant BA.1 control protease choice. We show that Y655 promotes S protein cleavage and cathepsin L-dependent entry while H655 jointly with N969 promotes TMPRSS2-dependent entry. These results define molecular signatures of SARS-CoV-2 protease choice and lung cell infection.