Cell surface glycan engineering reveals that matriglycan alone can recapitulate dystroglycan binding and function

Area of Science:

• Glycobiology
• Virology
• Molecular Biology

Background:

• α-Dystroglycan (α-DG) undergoes O-mannose glycosylation.
• Matriglycan, a repeating disaccharide (-Xylα1,3-GlcAβ1,3-)n, is a key modification of α-DG.
• Matriglycan serves as a receptor for laminin-G domains and is exploited by arenaviruses.

Purpose of the Study:

• To investigate the role of matriglycan chain length in binding interactions.
• To determine if matriglycan alone is sufficient for ligand binding and viral infection.
• To explore matriglycan as a potential target for antiviral strategies.

Main Methods:

• Chemoenzymatic synthesis of matriglycans for microarray printing.
• Enzymatic engineering of glycoproteins to introduce matriglycan.
• Cell-based assays using engineered cells and pseudoviruses.
• Inhibition assays with free matriglycan.

Main Results:

• Matriglycan demonstrated length-dependent binding to Laminin, Lassa virus GP1, and the IIH6 antibody.
• Engineered N-linked glycoproteins acquired IIH6 staining and Laminin binding.
• Matriglycan engineering on deficient cells restored Lassa-pseudovirus infection.
• Free matriglycan inhibited viral infection in a dose- and length-dependent manner.

Conclusions:

• Matriglycan is necessary and sufficient for binding Laminin, Lassa virus GP1, and mediating viral infection.
• Matriglycan acts as a tunable receptor, with longer chains enhancing ligand-binding capacity.
• These findings highlight matriglycan's critical role in viral pathogenesis and suggest therapeutic potential.