Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis PMID: 39984654

ADC Targets in Oncology

2026-04-10

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

Nat Cell Biol. 2025 Mar;27(3):449-463. doi: 10.1038/s41556-025-01616-x.

Ewan MacDonald ¹ ² ³ , Alison Forrester ¹ ⁴ ⁵ , Cesar A Valades-Cruz ¹ ⁶ ⁷ ⁸ , Thomas D Madsen ⁹ ¹⁰ , Joseph H R Hetmanski ¹¹ ¹² , Estelle Dransart ¹ ¹³ , Yeap Ng ⁹ , Rashmi Godbole ² ¹⁴ , Ananthan Akhil Shp ¹ ⁹ , Ludovic Leconte ⁶ ⁷ , Valérie Chambon ¹ , Debarpan Ghosh ¹ , Alexis Pinet ¹ , Dhiraj Bhatia ¹ ¹⁵ , Bérangère Lombard ¹⁶ , Damarys Loew ¹⁶ , Martin R Larsen ¹⁷ , Hakon Leffler ¹⁸ , Dirk J Lefeber ¹⁹ ²⁰ , Henrik Clausen ¹⁰ , Anne Blangy ²¹ , Patrick Caswell ¹¹ , Massiullah Shafaq-Zadah ¹ ¹³ , Satyajit Mayor ² ²² , Roberto Weigert ²³ , Christian Wunder ²⁴ ²⁵ , Ludger Johannes ²⁶ ²⁷

Affiliations

1. Cellular and Chemical Biology Unit, Institut Curie, Université PSL, U1143 INSERM, UMR3666 CNRS, Paris, France.
2. Cellular Organization and Signaling Group, National Centre for Biological Sciences, Bangalore, India.
3. Montpellier Cell Biology Research Center, CRBM, Université de Montpellier, CNRS, Montpellier, France.
4. WEL Research Institute, Wavre, Belgium.
5. Université de Namur ASBL, Namur, Belgium.
6. SERPICO Project Team, Inria-UMR144 CNRS Institut Curie, PSL Research University, Paris, France.
7. SERPICO Project Team, Inria Centre Rennes-Bretagne Atlantique, Rennes, France.
8. Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China.
9. Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
10. Department for Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark.
11. Wellcome Trust Centre for Cell-Matrix Research, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK.
12. Division of Biosciences, Department of Life Sciences, Centre for Genome Engineering and Maintenance, Brunel University London, London, UK.
13. SAIRPICO Project Team, Inria Center at University of Rennes, U1143 INSERM, Institut Curie, UMR3666 CNRS, PSL Research University, Paris, France.
14. The University of Trans-disciplinary Health Sciences and Technology (TDU), Bangalore, India.
15. Department of Biological Sciences and Engineering, Indian Institute of Technology Gandhinagar, Gujarat, India.
16. CurieCoreTech Spectrométrie de Masse Protéomique, Institut Curie, Université PSL, Paris, France.
17. Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
18. Section MIG (Microbiology, Immunology, Glycobiology), Department of Laboratory Medicine, Lund University, Lund, Sweden.
19. Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
20. Department of Human Genetics, Radboud Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
21. Montpellier Cell Biology Research Center (CRBM), Université de Montpellier, CNRS, Montpellier, France.
22. Centre for Mechanochemical Cell Biology, Warwick Medical School, University of Warwick, Warwick, UK.
23. Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. [email protected].
24. Cellular and Chemical Biology Unit, Institut Curie, Université PSL, U1143 INSERM, UMR3666 CNRS, Paris, France. [email protected].
25. SAIRPICO Project Team, Inria Center at University of Rennes, U1143 INSERM, Institut Curie, UMR3666 CNRS, PSL Research University, Paris, France. [email protected].
26. Cellular and Chemical Biology Unit, Institut Curie, Université PSL, U1143 INSERM, UMR3666 CNRS, Paris, France. [email protected].
27. SAIRPICO Project Team, Inria Center at University of Rennes, U1143 INSERM, Institut Curie, UMR3666 CNRS, PSL Research University, Paris, France. [email protected].

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.