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ERC

GALECTCOMPART Report Summary

Project ID: 340485
Funded under: FP7-IDEAS-ERC
Country: France

Mid-Term Report Summary - GALECTCOMPART (Endocytic Membrane Compartmentalization by Galectins)

How endocytic pits are built in processes of clathrin-independent endocytosis is one of the major outstanding questions in cellular membrane biology. We have shown that a cellular lectin, galectin-3 (Gal3), drives the glycosphingolipid (GSL)-dependent biogenesis of clathrin-independent carriers for the endocytic uptake of cargo proteins such as the adhesion and migration factors α5β1 integrin and CD44. On model membranes, Gal3 was found to be necessary and sufficient to induce the formation of narrow tubular invaginations in a strictly GSL-dependent manner. Based on these findings and our previous work on pathogenic lectins, we have suggested a novel hypothesis, termed GlycoLipid-Lectin (GL-Lect) hypothesis, according to which in some cases of endocytic uptake pit biogenesis is induced by the lectin-driven reorganization of GSLs and the co-clustering of glycosylated cargoes in such compositional GL-Lect type of nanoenvironments. We have shown that this mechanism operates in different cell types, including embryonic fibroblasts and T lymphocytes. Interestingly, the GL-Lect cargo protein α5β1 integrin follows the retrograde transport route from the plasma membrane to the Golgi apparatus, which we have then shown to be required for the polarized distribution of specifically the non-ligand-bound conformation of the protein to the leading edge of highly migratory cells. This selective trafficking is also observed with the bacterial GL-Lect cargoes Shiga and cholera toxin, pointing to a possible link between GL-Lect type of endocytosis and retrograde transport. Using Shiga toxin as a GL-Lect model protein, we also have identified a specific lectin-GSL geometry as a likely driver for membrane bending, and a number of cytosolic trafficking factors (endophilin-A2, the SNARE proteins syntaxin-2, 3 and 8, and the small GTPase Rab12) as being required for the processing of lectin-induced endocytic membrane invaginations. The study on endophilin-A2 has allowed us to propose a novel scission modality according to which BAR domain proteins form scaffolds on membrane invaginations, thereby imposing a diffusion barrier for lipids such that molecular motor-driven pulling on these scaffolded invaginations leads to tube thinning and eventually to scission. In summary, we strongly believe that the GL-Lect hypothesis has the potential to become a novel paradigm in membrane biology and glyco-sciences. The currently ongoing experiments in our groups are geared at exploring its full mechanistic and functional scope.

Contact

Sylvie LE COIDIC
Tel.: +33 1 56 24 65 14
Fax: +33 1 56 24 66 27
E-mail
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