Lipides, Nutrition, Cancer
Intervenant : Dr Ludger Johannes
Lectin-driven and glycosphingolipid-dependent construction of endocytic pits: Implications for cell polarity and persistent cell migrations
Background: Several endocytic processes do not require the activity of clathrin, and it has been a major question in membrane biology to know how the plasma membrane is bent and cargo proteins are sorted in these cases. Our previous studies have allowed us to propose a novel hypothesis: nanodomain construction by glycosphingolipid-binding lectin parts of toxins (e.g. Shiga and cholera toxins) or polyoma viruses (e.g. SV40) induces membrane curvature changes and drives the formation of endocytic pits for the cellular uptake of these pathogens or pathogenic factors (Nature 450, 670-675; NCB 12, 11-18). We could show that actin polymerization on Shiga toxin-induced endocytic tubules is sufficient to trigger scission in a process that requires domain boundary forces (Cell 140, 540-553). We are now analyzing how cortical actin dynamics contributes to the clustering of glycosphingolipid-lectin complexes on active membranes, thereby facilitating the nucleation of endocytic tubules exploiting fluctuation forces that had not been linked before to endocytosis. Another important aspect of our studies concerns the recognition of lectin-induced highly bent endocytic membrane invaginations by BAR domain proteins (Nature 517, 493), and the targeting to and fusion with endosomes of correspondingly generated endocytic carriers (JCS 128, 2891). Finally, we are studying cellular proteins that like the toxins use glycosphingolipids for endocytic membrane mechanics (NCB 16, 595), thereby regulating the cell surface dynamics of various markers with critical roles in cellular processes such as cell migration (NCB 18, 54). Our fundamental membrane biology research has incited us to explore the glycosphingolipidbinding B-subunit of Shiga toxin as antigen delivery tools for biomedical applications related to cancer immunotherapy (Science Translat Med 5, 172ra20). We are particularly exploring the mechanisms by which antigens are translocated across endosomal membranes to reach the cytosolic processing machinery (NRMCB 16, 311).
1. Shafaq-Zadah M. et al. Persistent cell migration and adhesion rely on retrograde transport of β(1) integrin. Nat. Cell. Biol. v. 18, p. 54-64, 2016.
2. Renard HF et al. Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis. Nature v. 517, p. 493-6, 2015.
3. Romer W. et al. Actin dynamics drive membrane reorganization and scission in clathrin-independent endocytosis. Cell v. 140, p. 540-43, 2010.
4. Lakshminarayan R et al. Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat. Cell. Biol., v. 16, p. 595-606, 2014.
5. Johannes L. et al. Building endocytic pits without clathrin. Nat. Rev. Mol. Cell. Biol., v. 16, p. 311-21, 2015.
Invitation: Olivier Micheau - UMR866
Le séminaire aura lieu à la faculté de médecine -Salle Klepping (3ème) à 11h00
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