O-linked sialoglycans modulate the proteolysis of SARS-CoV-2 spike and likely contribute to the mutational trajectory in variants of concern.
File(s)
Published version
Author(s)
Type
Journal Article
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 of VOC 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.
Date Issued
2023-03-22
Date Acceptance
2023-02-01
Citation
ACS Central Science, 2023, 9 (3), pp.393-404
ISSN
2374-7951
Publisher
American Chemical Society
Start Page
393
End Page
404
Journal / Book Title
ACS Central Science
Volume
9
Issue
3
Copyright Statement
Copyright © 2023 The Authors. Published by American Chemical Society. This work is published under a CC BY licence.
License URL
Identifier
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000935068100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=a2bf6146997ec60c407a63945d4e92bb
Subjects
BINDING
Chemistry
Chemistry, Multidisciplinary
CLEAVAGE
FAMILY
FURIN
GLYCOPROTEOME
GLYCOSYLATION
MEMBERS
Physical Sciences
Science & Technology
VIRUS
Publication Status
Published
Date Publish Online
2023-02-16