Differential endocytic trafficking of neuropathy-associated antibodies to GM1 ganglioside and cholera toxin in epithelial and neural cells

Abstract

Gangliosides are glycolipids mainly present at the plasma membrane (PM). Antibodies to gangliosides have been associated with a wide range of neuropathy syndromes. Particularly, antibodies to GM1 ganglioside are present in patients with Guillain-Barré syndrome (GBS). We investigated the binding and intracellular fate of antibody to GM1 obtained from rabbits with experimental GBS in comparison with the transport of cholera toxin (CTx), which binds with high affinity to GM1. We demonstrated that antibody to GM1 is rapidly and specifically endocytosed in CHO-K1 cells. After internalization, the antibody transited sorting endosomes to accumulate at the recycling endosome. Endocytosed antibody to GM1 is recycled back to the PM and released into the culture medium. In CHO-K1 cells, antibody to GM1 colocalized with co-endocytosed CTx at early and recycling endosomes, but not in Golgi complex and endoplasmic reticulum, where CTx was also located. Antibody to GM1, in contraposition to CTx, showed a reduced internalization to recycling endosomes in COS-7 cells and neural cell lines SH-SY5Y and Neuro2A. Results from photobleaching studies revealed differences in the lateral mobility of antibody to GM1 in the PM of analyzed cell lines, suggesting a relationship between the efficiency of endocytosis and lateral mobility of GM1 at the PM. Taken together, results indicate that two different ligands of GM1 ganglioside (antibody and CTx) are differentially endocytosed and trafficked, providing the basis to gain further insight into the mechanisms that operate in the intracellular trafficking of glycosphingolipid-binding toxins and pathological effects of neuropathy-associated antibodies.

Glycosphingolipids in HIV/AIDS: The Potential Therapeutic Application

“…This can be based on differential recognition of the hydroxyl groups within the sugar sequence as has been shown for Verotoxin variants and monoclonal antiGb 3 (Chark et al, 2004). Differential binding of anti-GM1 and cholera toxin to GM1 lipid isoforms has also been reported (Iglesias-Bartolome et al, 2009). This is consistent with differential ligand recognition of GSL lipid isoforms by ligands which bind the same carbohydrate sequence.…”

Anti-ganglioside antibody internalization attenuates motor nerve terminal injury in a mouse model of acute motor axonal neuropathy

“…Autoantibodies against membrane self antigens, including gangliosides, become endocytosed and undergo various intracellular trafficking fates (30,31). In some cases, Ab endocytosis accompanied by accelerated internalization of ligand may affect function (32).…”

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

“…Among these are found gangliosides, which are sialosylated glycosphingolipids mainly located in the outer layer of the plasma membrane of vertebrate cells (1, 2) and have been implicated in many physiological processes, including growth, differentiation, migration and apoptosis through modulating both cell signaling processes and cell-tocell and cell-to-matrix interactions (3-6). Furthermore, gangliosides have been associated with a wide range of pathological processes, being receptors for both viruses and antibodies (7,8).The biosynthesis of gangliosides is mainly carried out in the lumen of the Golgi cisternae by a complex system of membrane-bound glycolipid acceptors, nucleotide sugar donors, glycosyltransferases, and nucleotide sugar transporters (1, 9). These neosynthesized gangliosides move through the Golgi complex to the plasma membrane via the lumenal surface of transport vesicles (10 -12).…”

“…Among these are found gangliosides, which are sialosylated glycosphingolipids mainly located in the outer layer of the plasma membrane of vertebrate cells (1, 2) and have been implicated in many physiological processes, including growth, differentiation, migration and apoptosis through modulating both cell signaling processes and cell-tocell and cell-to-matrix interactions (3-6). Furthermore, gangliosides have been associated with a wide range of pathological processes, being receptors for both viruses and antibodies (7,8).…”