Targeting host O-linked glycan biosynthesis affects Ebola virus replication efficiency and reveals differential GalNAc-T acceptor site preferences on the Ebola virus glycoprotein
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View abstract on PubMed
Summary
This summary is machine-generated.Ebola virus glycoprotein (EBOV GP) O-glycosylation was mapped, revealing host GalNAc-T1
Area Of Science
- Virology
- Glycobiology
- Structural Biology
Background
- Ebola virus glycoprotein (EBOV GP) is extensively O-glycosylated, but its mucin-like domain structure and host glycosylation influence remain unclear.
- O-linked glycosylation is initiated by polypeptide GalNAc-transferases (GalNAc-Ts) with varying substrate specificities.
Purpose Of The Study
- To map O-glycosylation sites on EBOV GP.
- To investigate the role of host O-glycosylation capacity in EBOV replication.
- To explore potential therapeutic targets for modulating EBOV GP glycosylation.
Main Methods
- Tandem mass spectrometry to identify O-glycosites on EBOV GP.
- Quantitative differential O-glycoproteomics in wild-type and GalNAc-T deficient HEK293 cells.
- Authentic EBOV propagation in glycoengineered cell lines.
- Molecular dynamics simulations of the EBOV GP mucin-like domain.
Main Results
- Identified 47 O-glycosites on EBOV GP with similar patterns in different preparations.
- Found 12 O-glycosylated sites regulated by GalNAc-Ts, primarily GalNAc-T1.
- Demonstrated that host O-linked glycan initiation and elongation are crucial for viral particle production and progeny virus titers.
- Mapped O-glycan positions and structures, enabling molecular dynamics simulations.
Conclusions
- Host O-glycosylation, particularly initiated by GalNAc-T1, significantly impacts EBOV GP structure and EBOV replication.
- Targeting GALNT1 or C1GALT1C1 offers potential strategies for vaccine design and intervention by modulating EBOV GP O-glycan density.
- Glycoengineered cell lines are valuable tools for studying glycan-mediated mechanisms and guiding immune responses.
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Protein glycosylation starts in the ER lumen and continues in the Golgi apparatus. Glycosyltransferases catalyze the addition of sugar molecules or glycosylation of proteins. Usually, these enzymes add sugars to the hydroxyl groups of selected serine or threonine residues to form O-linked glycans or the amino groups of asparagine residues to form N-linked glycans. Different positions on the same polypeptide chain can contain differently linked glycans.
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Glycans, a class of complex heterogeneous molecules, can be covalently attached to proteins to form glycosylated proteins that regulate various physiological and pathological processes. Glycosylated proteins or glycoproteins comprise N-linked and O-linked oligosaccharides. O-glycosylation is the most common type of protein glycosylation. Here, glycans attach to the oxygen atom of the hydroxyl groups of Serine or Threonine residues. O-linked glycosylation occurs later in protein processing,...
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