title: Glycolipid trafficking in Drosophila undergoes pathway switching in response to aberrant cholesterol levels.
abstract: In lipid storage diseases, the intracellular trafficking of sphingolipids is altered by conditions of aberrant cholesterol accumulation. Drosophila has been used recently to model lipid storage diseases, but the effects of sterol accumulation on sphingolipid trafficking are not known in the fly, and the trafficking of sphingolipids in general has not been studied in this model organism. Here, we examined the uptake and intracellular distribution of a fluorescent glycolipid analog, BODIPY-lactosyl-ceramide, in Drosophila neurons. The uptake mechanism and intracellular trafficking route of this simple glycolipid are largely conserved. Our principle finding is that cholesterol steers trafficking of the glycolipid between Golgi, lysosome, and recycling compartments. Our analyses support the idea that cholesterol storage in Drosophila triggers a switch in glycolipid trafficking from the biosynthetic to the degradative endolysosomal pathway, whereas cholesterol depletion eliminates recycling of the glycolipid. Unexpectedly, we observe a novel phenomenon we term "hijacking," whereby lactosyl-ceramide diverts the trafficking pathway of an endocytic cargo, dextran, completely away from its lysosomal target. This work establishes that glycolipid trafficking in Drosophila undergoes changes similar to those seen in mammalian cells under conditions of cholesterol storage and therefore validates Drosophila as a suitable model organism in which to study lipid storage diseases.
authors.affiliation: Institute of Bioengineering and Nanotechnology, Agency for Science, Technology, and Research, Singapore.
authors.forename: Ralf
authors.initials: R
authors.lastname: Hortsch
authors.forename: Esther
authors.initials: E
authors.lastname: Lee
authors.forename: Nandanan
authors.initials: N
authors.lastname: Erathodiyil
authors.forename: Sarita
authors.initials: S
authors.lastname: Hebbar
authors.forename: Steffen
authors.initials: S
authors.lastname: Steinert
authors.forename: Jun Yu
authors.initials: JY
authors.lastname: Lee
authors.forename: Doreen See Kin
authors.initials: DS
authors.lastname: Chua
authors.forename: Rachel
authors.initials: R
authors.lastname: Kraut
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000737:chemistry; D001896:Boron Compounds / Q000737:chemistry; D002784:Cholesterol / Q000737:chemistry*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004705:Endocytosis; D006017:Glycolipids / Q000737:chemistry*; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000737:chemistry; D007790:Lactosylceramides / Q000737:chemistry; D008055:Lipids / Q000737:chemistry; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D008956:Models, Chemical; D009474:Neurons / Q000378:metabolism
chemical_list: C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D015703:Antigens, CD; D001896:Boron Compounds; D006017:Glycolipids; D007790:Lactosylceramides; D008055:Lipids; D049452:Green Fluorescent Proteins; C009744:CDw17 antigen; D002784:Cholesterol