O-Linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutational trajectory in variants of concern. Gonzalez-Rodriguez, E., Zol-Hanlon, M., Bineva-Todd, G., Marchesi, A., Skehel, M., Mahoney, K. E, Roustan, C., Borg, A., Vagno, L. D., Kjær, S., Wrobel, A. G, Benton, D. J, Nawrath, P., Flitsch, S. L, Joshi, D., González-Ramírez, A. M., Wilkinson, K. A, Wilkinson, R. J, Wall, E. C, Hurtado-Guerrero, R., Malaker, S. A, & Schumann, B. ACS Central Science, American Chemical Society, feb, 2023. ![O-Linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutational trajectory in variants of concern [link]](https://bibbase.org/img/filetypes/link.svg "link")
Paper doi abstract bibtex The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides furin, spikes from these variants appear to rely on other proteases for maturation, including TMPRSS2. Glycans near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, we identify that sialic acid-containing O-linked glycans on Thr678 of SARS-CoV-2 spike influence furin and TMPRSS2 cleavage and posit O-linked glycosylation as a likely driving force for the emergence ofVOC mutations. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, an event that is suppressed by mutations in the VOCs Alpha, Delta, and Omicron. We found that the sole incorporation of N-acetylgalactosamine did not impact furin activity in synthetic O-glycopeptides, but the presence of sialic acid reduced the furin rate by up to 65%. Similarly, O-glycosylation with a sialylated trisaccharide had a negative impact on TMPRSS2 cleavage. With a chemistry-centered approach, we substantiate O-glycosylation as a major determinant of spike maturation and propose disruption of O-glycosylation as a substantial driving force for VOC evolution.
@article{Gonzalez-Rodriguez2023,
abstract = {The emergence of a polybasic cleavage motif for the protease furin in SARS-CoV-2 spike has been established as a major factor for human viral transmission. The region N-terminal to that motif is extensively mutated in variants of concern (VOCs). Besides furin, spikes from these variants appear to rely on other proteases for maturation, including TMPRSS2. Glycans near the cleavage site have raised questions about proteolytic processing and the consequences of variant-borne mutations. Here, we identify that sialic acid-containing O-linked glycans on Thr678 of SARS-CoV-2 spike influence furin and TMPRSS2 cleavage and posit O-linked glycosylation as a likely driving force for the emergence ofVOC mutations. We provide direct evidence that the glycosyltransferase GalNAc-T1 primes glycosylation at Thr678 in the living cell, an event that is suppressed by mutations in the VOCs Alpha, Delta, and Omicron. We found that the sole incorporation of N-acetylgalactosamine did not impact furin activity in synthetic O-glycopeptides, but the presence of sialic acid reduced the furin rate by up to 65{\%}. Similarly, O-glycosylation with a sialylated trisaccharide had a negative impact on TMPRSS2 cleavage. With a chemistry-centered approach, we substantiate O-glycosylation as a major determinant of spike maturation and propose disruption of O-glycosylation as a substantial driving force for VOC evolution.},
author = {Gonzalez-Rodriguez, Edgar and Zol-Hanlon, Mia and Bineva-Todd, Ganka and Marchesi, Andrea and Skehel, Mark and Mahoney, Keira E and Roustan, Chlo{\"{e}} and Borg, Annabel and Vagno, Lucia Di and Kj{\ae}r, Svend and Wrobel, Antoni G and Benton, Donald J and Nawrath, Philipp and Flitsch, Sabine L and Joshi, Dhira and Gonz{\'{a}}lez-Ram{\'{i}}rez, Andr{\'{e}}s Manuel and Wilkinson, Katalin A and Wilkinson, Robert J and Wall, Emma C and Hurtado-Guerrero, Ram{\'{o}}n and Malaker, Stacy A and Schumann, Benjamin},
doi = {10.1021/ACSCENTSCI.2C01349},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Gonzalez-Rodriguez et al. - 2023 - O-Linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutat.pdf:pdf},
issn = {2374-7943},
journal = {ACS Central Science},
keywords = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
mendeley-tags = {OA,OA{\_}PMC,fund{\_}ack,genomics{\_}fund{\_}ack,original},
month = {feb},
pages = {10.1021/acscentsci.2c01349},
pmid = {36968546},
publisher = {American Chemical Society},
title = {{O-Linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutational trajectory in variants of concern}},
url = {https://pubs.acs.org/doi/full/10.1021/acscentsci.2c01349},
year = {2023}
}
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