Fusobacterium nucleatum Lipopolysaccharides Disrupt the Interaction of Siglec-7 to Sialoglycans Expressed on Mammalian Cells

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Abstract
Sialic acid-binding immunoglobulin-like lectins (Siglecs) are key immune receptors that bind to cell surface sialic acids, leading to modulation of the immune system. Interrupting the Siglec–sialoglycan binding in cancer has been proposed as a potential antitumor response strategy. We previously showed that colon-cancer-associated Fusobacterium nucleatum (Fn) ATCC 51191 interacts with Siglec-7 via its lipopolysaccharide (LPS), revealing Fn LPS as a new ligand for Siglec-7. Here, we used glycoengineered cells carrying sialic acid variants to investigate the capacity of LPS isolated from F. nucleatum strains to disrupt the interaction between sialic acid expressed on mammalian cells and Siglec-7. We first showed that LPS extracted from Fusobacterium polymorphum ATCC 10953, F. nucleatum ssp. animalis ATCC 51191, and F. nucleatum ssp. nucleatum ATCC 25586 strains bound to recombinant Siglec-7 in vitro, while no binding was observed with the Siglec-7R124A mutant, suggesting that the binding occurred through the carbohydrate binding V-set domain. Using glycoengineered Jurkat cells and HEK293T cells carrying modified sialic acid forms, we demonstrated that F. nucleatum LPS could significantly disrupt the binding of Siglec-7 to these cells and that this inhibition was decreased following neuraminidase treatment, confirming that the interaction between Fn LPS and Siglec-7 is carbohydrate-mediated. We further validated these data using Jurkat cells and HEK293T cells expressing high-affinity sialic acid ligands. We showed that F. nucleatum LPS significantly disrupted the binding of Siglec-7 to these cells in a specific manner. These findings offer novel insights into the development of glycomimetic approaches for limiting colon cancer progression.
Funding Information
  • H2020 Marie Skłodowska-Curie Actions (956758)
  • Biotechnology and Biological Sciences Research Council (BB/X011054/1)

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