ABC Transporters Can Regulate Glycosphingolipid Biosynthesis within the Golgi

Abstract

Several ABC membrane transporters are key components in glycosphingolipid anabolism in cell culture. We proposed these transporters can all act as (in part, redundant) glucosyl ceramide (GlcCer) lipid flippases within the Golgi cysternae to translocate cytosolic membrane GlcCer to provide differentially distributed luminal GSL (glycosphingolipid) precursor pools. Distinct LacCer pools thus generated within the Golgi stack, could provide separate precursor pools for the differential synthesis of the various complex GSL series, according to GSL glycosyl transferase intracysternal topological distribution. We now show several important corollaries for ABC transporter mediated GSL biosynthesis. a) Knockdown of ABCB1 and the cytosolic GlcCer transporter, FAPP2(four-phosphate adaptor protein 2) have distinct effects, b) the role of ABCB1 (and FAPP2) in GSL anabolism varies between cell types, suggesting cell type selective ABC GlcCer transporter roles, c) Our previously reported enchanced GlcCer and Lc₃Cer synthesis following statin-mediated cholesterol depletion, which induces GlcCer synthase relocation within the Golgi, is blocked by ABCB1 knockdown d) known ABCB1 substrates can modulate cellular GSL biosynthesis. Pathways which regulate ABC transporter expression can therefore impinge GSL biosynthesis