Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis

Abstract

Glycolipid-lectin-driven endocytosis controls the formation of clathrin-independent carriers and the internalization of various cargos such as β1 integrin. Whether this process is regulated in a dynamic manner remained unexplored. Here we demonstrate that, within minutes, the epidermal growth factor triggers the galectin-driven endocytosis of cell-surface glycoproteins, such as integrins, that are key regulators of cell adhesion and migration. The onset of this process—mediated by the Na+/H+ antiporter NHE1 as well as the neuraminidases Neu1 and Neu3—requires the pH-triggered enzymatic removal of sialic acids whose presence otherwise prevents galectin binding. De-sialylated glycoproteins are then retrogradely transported to the Golgi apparatus where their glycan make-up is reset to regulate EGF-dependent invasive-cell migration. Further evidence is provided for a role of neuraminidases and galectin-3 in acidification-dependent bone resorption. Glycosylation at the cell surface thereby emerges as a dynamic and reversible regulatory post-translational modification that controls a highly adaptable trafficking pathway. MacDonald et al. show that EGF triggers de-sialylation of plasma membrane glycoproteins like integrins in a mechanism that depends on the Na+/H+ antiporter NHE1 and the neuraminidases Neu1 and Neu3. Integrins are trafficked to the Golgi and re-sialylated.