2. Academic Validation
  3. Growth factor-triggered de-sialylation controls glycolipid-lectin-driven endocytosis

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

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. weigertr@mail.nih.gov.
  • 24 Cellular and Chemical Biology Unit, Institut Curie, Université PSL, U1143 INSERM, UMR3666 CNRS, Paris, France. christian.wunder@curie.fr.
  • 25 SAIRPICO Project Team, Inria Center at University of Rennes, U1143 INSERM, Institut Curie, UMR3666 CNRS, PSL Research University, Paris, France. christian.wunder@curie.fr.
  • 26 Cellular and Chemical Biology Unit, Institut Curie, Université PSL, U1143 INSERM, UMR3666 CNRS, Paris, France. ludger.johannes@curie.fr.
  • 27 SAIRPICO Project Team, Inria Center at University of Rennes, U1143 INSERM, Institut Curie, UMR3666 CNRS, PSL Research University, Paris, France. ludger.johannes@curie.fr.
PMID: 39984654 DOI: 10.1038/s41556-025-01616-x
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.

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