Glycosphingolipid functions

Glycosphingolipids are concentrated in lipid rafts, which are dynamic membrane microdomains rich in cholesterol. Some proteins like GPI-anchored proteins also partition into lipid rafts. Because of their dynamism and their movements in membranes, it is difficult to study the functional relevance of lipid rafts. The glycosphingolipid GM1 is commonly used as marker for these rafts, which are enriched at sites of endocytosis at the plasma membrane and at sites of vesicular budding in intracellular membranes. In lipid rafts, glycosphingolipids associate with signaling proteins. These interactions take place either directly when the signaling protein harbors a carbohydrate-binding domain, or through surface binary lectins like galectins, which cross-link the surface glycoproteins with surrounding glycosphingolipids. Such associations affect the signaling intensity of several surface receptor complexes, as for example observed in the context of the T-cell receptor activated by antigen-presenting cells.

FIG: CONCEPT SIGNALING AND GSL

Several gangliosides influence various signaling pathways. In some cases, structurally similar gangliosides act in opposite way on a same signaling protein. For example, GM3 decreases tyrosine phosphorylation mediated by activation of the EGF-receptor, whereas de-N-acetylated-GM3 increases tyrosine phosphorylation on the same receptor. The mechanisms underlying the effect of gangliosides on receptor activation remain however largely unknown.

Some viruses and toxins also use glycosphingolipids for docking on target cells and transport into cellular compartments. Tetanus and botulinum toxins bind to the ganglioside GT1b, Shiga toxin to the globosides Gb3 and both the SV40 virus and cholera toxin bind to the ganglioside GM1. Because glycosphingolipids shuttle rapidly between the plasma membrane and the ER, they are ideal carriers for toxins requiring delivery to the cytosol and nucleus. In the case of cholera toxin, the enzymatically active subunit A dissociates from the GM1-binding subunit B in the ER and then exits the ER to the cytosol by passage through the Sec61 translocon.