ATP-binding cassette transporters mediate differential biosynthesis of glycosphingolipid species

Abstract

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ATP-Binding Cassette Transporter Family C Protein 10 Participates in the Synthesis and Efflux of Hexosylceramides in Liver Cells

“…The current report indicates that ABCC10 plays a role in the synthesis of HexCer. Consistent with our studies, Budani et al [ 20 ] identified several ABC transporters that may play roles as flippases and affect synthesis. These observations point out to the possibility that, besides being drug/molecule exporters, ABC transporters might be physiologically important modulators of sphingolipid biosynthesis.…”

“…It is presumed that this translocation of GlcCer from the cytosol to lumen is mediated by multiple Golgi and trans Golgi network flippases [ 12 , 16 , 18 , 19 ]. Recently, Budani et al [ 20 ] showed that multiple ABC transporters potentially act as GlcCer flippases and differentially control glycosphingolipids biosynthesis. It is likely that there are more proteins that regulate HexCer synthesis.…”

Role of Globotriaosylceramide in Physiology and Pathology

“…The synthesis of the ceramide molecule from the sphingosine and the fatty acid takes place in the cytosolic aspects of the endoplasmic reticulum membranes by ceramide synthases (CerS1-6) ( Rizzo et al, 2021 ). The synthesis of the oligosaccharide part of Gb3 takes place in the Golgi apparatus ( Budani et al, 2021 ; Rizzo et al, 2021 ) and is constituted firstly by the synthesis of a glucosylceramide (GlcCer) produced by the enzyme glucosylceramide synthase (GCS), which catalyzes the binding of a glucose molecule to a ceramide; next, the enzyme β-1,4 galactosyltransferase 5 (β4Gal-T5) binds one molecule of galactose to form lactosylceramide (LacCer); in a third and final reaction, the enzyme lactosylceramide α-1,4-galactosyltransferase (Gb3 synthase) catalyzes the addition of α-1,4 galactose to LacCer (galactose β-1,4 glucose 1-1′ Cer) to produce Gb3 (galactose α-1,4 galactose β-1,4 glucose 1,1′ Cer) ( Kojima et al, 2000 ; Okuda and Nakayama, 2008 ; Budani et al, 2021 ; Rizzo et al, 2021 ). Another enzyme, isoglobotriaosylceramide synthase, can produce polygalactosylated species (Galn-Gb3) by adding α-1,3 galactose residues to Gb3 ( Miller et al, 2018 ).…”

“…On the other hand, in vesicular transport (which has been proposed for the synthesis of GSLs of the ganglio-series), the newly synthesized GlcCer in the Golgi luminal leaflet is translocated to the luminal leaflet by an ATP-dependent flippase and delivered to trans Golgi via vesicular transport. Regardless of the route taken (vesicular or non-vesicular), once GlcCer reaches the luminal side of the trans Golgi membrane, it becomes the substrate of β4Gal-T5 with the formation of LacCer, a precursor for the synthesis of globo-, ganglio-, lacto- and neolacto-series of GSLs ( Budani et al, 2021 ; Rizzo et al, 2021 ).…”

Differential Regulation of Glucosylceramide Synthesis and Efflux by Golgi and Plasma Membrane Bound ABCC10

“…Once GlcCer is synthesized in the cytosol, it is translocated towards the Golgi lumen for the synthesis of other GSLs by multiple Golgi and Trans Golgi Network flippases [ 9 , 11 , 12 , 13 ]. Recently, it was shown that multiple ABC transporters differentially regulate GSL biosynthesis by acting as GlcCer flippases [ 14 ]. Furthermore, ABCC1 and ABCA12 have been shown to transport GlcCer in vitro [ 15 ] and in keratinocytes [ 16 ].…”