ABSTRACT
Galectins are glycan-binding proteins translating the sugar-encoded information of cellular glycoconjugates into physiological activities, including immunity, cell migration, and signaling. Galectins also interact with non-glycosylated partners in the extracellular milieu, among which the pre-B cell receptor (pre-BCR) during B cell development. How these interactions might interplay with the glycan-decoding function of galectins is unknown. Here, we perform NMR experiments on native membranes to monitor Gal-1 binding to physiological cell surface ligands. We show that pre-BCR interaction changes Gal-1 binding to glycosylated pre-B cell surface receptors. At the molecular and cellular levels, we identify α2,3-sialylated motifs as key targeted epitopes. This targeting occurs through a selectivity switch increasing Gal-1 contacts with α2,3-sialylated poly-N-acetyllactosamine upon pre-BCR interaction. Importantly, we observe that this switch is involved in the regulation of pre-BCR activation. Altogether, this study demonstrates that interactions to non-glycosylated proteins regulate the glycan-decoding functions of galectins at the cell surface.
Subject(s)
Galectin 1 , Pre-B Cell Receptors , Galectin 1/metabolism , Humans , Pre-B Cell Receptors/metabolism , Protein Binding , Glycosylation , Cell Membrane/metabolism , Animals , Polysaccharides/metabolism , MiceABSTRACT
Galectins are versatile glycan-binding proteins involved in immunomodulation. Evidence suggests that galectins can control the immunoregulatory function of cytokines and chemokines through direct binding. Here, we report on an inverse mechanism in which chemokines control the immunomodulatory functions of galectins. We show the existence of several specific galectin-chemokine binding pairs, including galectin-1/CXCL4. NMR analyses show that CXCL4 binding induces changes in the galectin-1 carbohydrate binding site. Consequently, CXCL4 alters the glycan-binding affinity and specificity of galectin-1. Regarding immunomodulation, CXCL4 significantly increases the apoptotic activity of galectin-1 on activated CD8+ T cells, while no effect is observed in CD4+ T cells. The opposite is found for another galectin-chemokine pair, i.e., galectin-9/CCL5. This heterodimer significantly reduces the galectin-9 induced apoptosis of CD4+ T cells and not of CD8+ T cells. Collectively, the current study describes an immunomodulatory mechanism in which specific galectin-chemokine interactions control the glycan-binding activity and immunoregulatory function of galectins.