<i>Fusobacterium nucleatum</i> Lipopolysaccharides O-Antigen Defines a Novel Siglec-7 Binding Epitope

<i>Fusobacterium nucleatum</i> (<i>Fn</i>) is a Gram-negative bacterium predominantly found in the human oral cavity, occasionally linked to systemic diseases, including colorectal cancer. Bacterial lipopolysaccharides (LPSs) represent one of the possible virulence factors contributing to and promoting disease progression. <i>Fn</i> LPS is recognized by Siglec-7, a sialic acid-binding inhibitory receptor expressed on immune cells and promising novel target for cancer immunotherapy. Through a combined approach of structural biology, biophysics, NMR, and computational methods, we explored the molecular basis of the interaction between Siglec-7 and the LPS from<i>F. nucleatum</i> <i>ssp polymorphum</i> 10953, whose O-antigen contains peculiar sugars such as the neuraminic acid and the AAT (FucpNAc4N). We discovered a novel Siglec-7 binding epitope within the LPS O-antigen repeating unit, defined by its internal sialic acid and AAT residues. We propose a wing-like movement of the O-antigen, where Siglec-7 BC and CC' loops alternately engage the O-antigen edges within the binding site, with the BC loop forming more stable interactions. We uncover a novel <i>Fn</i>10953 immune evasion mechanism and highlight Siglec-7 and LPS as novel therapeutic targets for <i>Fn</i>-associated CRC, providing new avenues for intervention.

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Publication Details

Journal
JACS Au
Published
2025-09-25
DOI
https://doi.org/10.1021/jacsau.5c00810
Citations
2
Primary Topic
Glycosylation and Glycoproteins Research
Type
article
Field-Weighted Citation Impact
1.61
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article

Fusobacterium nucleatum Lipopolysaccharides O-Antigen Defines a Novel Siglec-7 Binding Epitope

Dimitra Lamprinaki, Giulia Roxana Gheorghita, Nathalie Juge, Celeste Abreu et al.
2 citations
JACS Au
Glycosylation and Glycoproteins Research
1.61
article

Fusobacterium nucleatum Lipopolysaccharides O-Antigen Defines a Novel Siglec-7 Binding Epitope

Dimitra Lamprinaki, Giulia Roxana Gheorghita, Nathalie Juge, Celeste Abreu, Giovanni Smaldone, Cristina Di Carluccio, Antonio Molinaro, Lorena Buono, Ondřej Vaněk, Ferran Nieto‐Fabregat, A. Masi, Linda Cerofolini, Marco Fragai, Alba Silipo, Roberta Marchetti, Muhammad Ali, Luis Padilla‐Cortés
article en
2 citations

Abstract

<i>Fusobacterium nucleatum</i> (<i>Fn</i>) is a Gram-negative bacterium predominantly found in the human oral cavity, occasionally linked to systemic diseases, including colorectal cancer. Bacterial lipopolysaccharides (LPSs) represent one of the possible virulence factors contributing to and promoting disease progression. <i>Fn</i> LPS is recognized by Siglec-7, a sialic acid-binding inhibitory receptor expressed on immune cells and promising novel target for cancer immunotherapy. Through a combined approach of structural biology, biophysics, NMR, and computational methods, we explored the molecular basis of the interaction between Siglec-7 and the LPS from<i>F. nucleatum</i> <i>ssp polymorphum</i> 10953, whose O-antigen contains peculiar sugars such as the neuraminic acid and the AAT (FucpNAc4N). We discovered a novel Siglec-7 binding epitope within the LPS O-antigen repeating unit, defined by its internal sialic acid and AAT residues. We propose a wing-like movement of the O-antigen, where Siglec-7 BC and CC' loops alternately engage the O-antigen edges within the binding site, with the BC loop forming more stable interactions. We uncover a novel <i>Fn</i>10953 immune evasion mechanism and highlight Siglec-7 and LPS as novel therapeutic targets for <i>Fn</i>-associated CRC, providing new avenues for intervention.

JACS AuVol. 5(11)
Charles University (CZ), Norwich Research Park (GB), Quadram Institute (GB), Federico II University Hospital (IT), CEINGE Biotecnologie Avanzate Franco Salvatore (Italy) (IT), Interuniversity Consortium for Magnetic Resonance (IT), Giotto Biotech (Italy) (IT), University of Naples Federico II (IT)
Openalex Percentile: Top 15%
Glycosylation and Glycoproteins Research
1.61
DOIOpen Access PDFOpenAlex
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