Siglec-7 and -15 recognize repeated clustered sulfo-sialo O-glycan motifs on select O-glycoproteins

Authors

Goerdeler, F., Hornikx, D. L. A. H., Valckx, V. T. C., Chien, Y.-C., de Wit, D., Jaroentomeechai, T., Jaeger, M., Furukawa, S., Tseng, H.-C., Jung, J., Schmidt, E. N., Khoo, K.-H., Miller, R. L., Germeraad, W. T. V., Bos, G. M. J., Macauley, M. S., Clausen, H., Bull, C., Narimatsu, Y.

Abstract

Siglecs are key immunoreceptors in immune homeostasis and cancer immunosuppression. Diverse endogenous and exogenous sialoglycan ligands induce Siglec-mediated immunoregulation, but the nature of endogenous Siglec ligands and how seemingly ubiquitous sialoglycans achieve selectivity is unclear. Here, we employed a HEK293 cell-based array and glycoprotein reporters designed from human mucins and mucin-like proteins with O-glycans in natural clusters and repeat motifs to dissect specificities of Siglec-7 and -15. We first used precomplexed Siglec-Fc chimera to demonstrate that CHST1-mediated 6-O-sulfation markedly enhanced binding to select O-glycoproteins, namely MAdCAM1, CD43, and PSGL-1. Probing binding properties of Siglec-7 expressed exogenously on CHO cells or endogenously on human monocytes by reverse assays employing fluorophore-tagged O-glycoprotein reporters revealed specific binding to the sulfo-sialyl core1 O-glycoform of the same O-glycoproteins. Our study indicates that Siglec-7 on immune cells employs multivalent interactions with repeated motifs of clustered sulfo-sialyl O-glycans to drive selectivity in ligand interactions and Siglec-induced immunosuppression.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 09 Jan 2026.

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