PMID- 34597626
OWN - NLM
STAT- MEDLINE
DCOM- 20220324
LR  - 20231108
IS  - 1539-7262 (Electronic)
IS  - 0022-2275 (Print)
IS  - 0022-2275 (Linking)
VI  - 62
DP  - 2021
TI  - ATP-binding cassette transporters mediate differential biosynthesis of 
      glycosphingolipid species.
PG  - 100128
LID - S0022-2275(21)00110-3 [pii]
LID - 10.1016/j.jlr.2021.100128 [doi]
LID - 100128
AB  - The cytosolic-oriented glucosylceramide (GlcCer) synthase is enigmatic, requiring 
      nascent GlcCer translocation to the luminal Golgi membrane to access 
      glycosphingolipid (GSL) anabolic glycosyltransferases. The mechanism by which 
      GlcCer is flipped remains unclear. To investigate the role of GlcCer-binding 
      partners in this process, we previously made cleavable, biotinylated, 
      photoreactive GlcCer analogs in which the reactive nitrene was closely apposed to 
      the GlcCer head group, while maintaining a C16-acyl chain. GlcCer-binding protein 
      specificity was validated for both photoprobes. Using one probe, XLB, here we 
      identified ATP-binding cassette (ABC) transporters ABCA3, ABCB4, and ABCB10 as 
      unfractionated microsomal GlcCer-binding proteins in DU-145 prostate tumor cells. 
      siRNA knockdown (KD) of these transporters differentially blocked GSL synthesis 
      assessed in toto and via metabolic labeling. KD of ABCA3 reduced acid/neutral GSL 
      levels, but increased those of LacCer, while KD of ABCB4 preferentially reduced 
      neutral GSL levels, and KD of ABCB10 reduced levels of both neutral and acidic 
      GSLs. Depletion of ABCA12, implicated in GlcCer transport, preferentially 
      decreased neutral GSL levels, while ABCB1 KD preferentially reduced gangliosides, 
      but increased neutral GSL Gb(3). These results imply that multiple ABC 
      transporters may provide distinct but overlapping GlcCer and LacCer pools within 
      the Golgi lumen for anabolism of different GSL series by metabolic channeling. 
      Differential ABC family member usage may fine-tune GSL biosynthesis depending on 
      cell/tissue type. We conclude that ABC transporters provide a new tool for the 
      regulation of GSL biosynthesis and serve as potential targets to reduce selected 
      GSL species/subsets in diseases in which GSLs are dysregulated.
CI  - Crown Copyright (c) 2021. Published by Elsevier Inc. All rights reserved.
FAU - Budani, Monique
AU  - Budani M
AD  - Division of Molecular Medicine, Research Institute, Hospital for Sick Children, 
      Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, 
      University of Toronto, Toronto, Ontario, Canada.
FAU - Auray-Blais, Christiane
AU  - Auray-Blais C
AD  - Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine and 
      Health Sciences, Universite de Sherbrooke, Quebec, Canada.
FAU - Lingwood, Clifford
AU  - Lingwood C
AD  - Division of Molecular Medicine, Research Institute, Hospital for Sick Children, 
      Toronto, Ontario, Canada; Department of Laboratory Medicine & Pathobiology, 
      University of Toronto, Toronto, Ontario, Canada; Department of Biochemistry, 
      University of Toronto, Toronto, Ontario, Canada. Electronic address: 
      cling@sickkids.on.ca.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210928
PL  - United States
TA  - J Lipid Res
JT  - Journal of lipid research
JID - 0376606
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Glycosphingolipids)
SB  - IM
MH  - ATP-Binding Cassette Transporters/*metabolism
MH  - Glycosphingolipids/*biosynthesis
MH  - Humans
MH  - Tumor Cells, Cultured
PMC - PMC8569594
OTO - NOTNLM
OT  - ABC transporter
OT  - GSL anabolism
OT  - GlcCer pools
OT  - GlcCer synthase
OT  - LacCer
OT  - glucosylceramide flippase
OT  - glycosphingolipid
OT  - metabolic channeling
OT  - metabolic labeling
OT  - photoprobes
COIS- Conflict of interest The authors declare that they have no conflicts of interest 
      with the contents of this article.
EDAT- 2021/10/02 06:00
MHDA- 2022/03/25 06:00
PMCR- 2021/09/28
CRDT- 2021/10/01 20:14
PHST- 2021/03/25 00:00 [received]
PHST- 2021/08/18 00:00 [revised]
PHST- 2021/09/03 00:00 [accepted]
PHST- 2021/10/02 06:00 [pubmed]
PHST- 2022/03/25 06:00 [medline]
PHST- 2021/10/01 20:14 [entrez]
PHST- 2021/09/28 00:00 [pmc-release]
AID - S0022-2275(21)00110-3 [pii]
AID - 100128 [pii]
AID - 10.1016/j.jlr.2021.100128 [doi]
PST - ppublish
SO  - J Lipid Res. 2021;62:100128. doi: 10.1016/j.jlr.2021.100128. Epub 2021 Sep 28.