The Regulation of Ganglioside GM3 Synthesis

Abstract

Glycosphingolipids (GSLs) exist in the outer leaflet of the plasma membrane, where they form lipid microdomains that function as platforms for the regulation of trans-membrane signal transduction. In mammals, complex GSLs differing in the number and/or type of sugar species are produced in a cell-type specific manner, and the variety of glycan structures in GSLs are believed to determine specific cell functions. The glycan moieties of GSLs are synthesized at the luminal side of the Golgi apparatus by multiple Golgi-resident glycosyltransferases. Since the expression levels of most endogenous glycosyltransferases are relatively low, their detection is generally difficult. Nevertheless, we have succeeded in detecting endogenous mouse GM3 synthase (GM3S), the primary glycosyltransferase responsible for the biosynthesis of ganglio-series gangliosides. Mouse GM3S (mGM3S) has three isoforms (M1-GM3S, M2-GM3S, and M3-GM3S), each with a distinct length in its NH2-terminal cytoplasmic tail. These isoforms are produced by leaky scanning from two mRNA variants, mGM3Sa and mGM3Sb. M1-GM3S is stably localized in the endoplasmic reticulum (ER), as a result of retrograde transport signals (arginine [R]-based motifs); consequently, its in vivo GM3 synthesis activity is very low compared with that of other isoforms. In contrast, both M2-GM3S and M3-GM3S are localized in the Golgi apparatus, yet each exhibits a distinct intracellular fate. M2-GM3S is rapidly degraded in the lysosomes, whereas M3-GM3S is retained in the Golgi apparatus. A system that produces GM3S isoforms having such distinct characteristics is likely to be of critical importance in the regulation of GM3 biosynthesis under various pathological and physiological conditions.