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J. Cell Biol. 192 (4): 557-567

Copyright © 2011 by the Rockefeller University Press.

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Sphingosine kinases and their metabolites modulate endolysosomal trafficking in photoreceptors

Ikuko Yonamine1,2, Takeshi Bamba3, Niraj K. Nirala1,2, Nahid Jesmin1,2, Teresa Kosakowska-Cholody4, Kunio Nagashima5, Eiichiro Fukusaki3, Jairaj K. Acharya4, , and Usha Acharya1,2

1 Program in Gene Function and Expression and 2 Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605
3 Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
4 Laboratory of Cell and Developmental Signaling, National Cancer Institute, Frederick, MD 21702
5 Electron Microscopy Facility and Image Analysis Laboratory, Science Applications International Corporation–Frederick, Frederick, MD 21702

Correspondence to Usha Acharya: usha.acharya{at}umassmed.edu

Abstract: Internalized membrane proteins are either transported to late endosomes and lysosomes for degradation or recycled to the plasma membrane. Although proteins involved in trafficking and sorting have been well studied, far less is known about the lipid molecules that regulate the intracellular trafficking of membrane proteins. We studied the function of sphingosine kinases and their metabolites in endosomal trafficking using Drosophila melanogaster photoreceptors as a model system. Gain- and loss-of-function analyses show that sphingosine kinases affect trafficking of the G protein–coupled receptor Rhodopsin and the light-sensitive transient receptor potential (TRP) channel by modulating the levels of dihydrosphingosine 1 phosphate (DHS1P) and sphingosine 1 phosphate (S1P). An increase in DHS1P levels relative to S1P leads to the enhanced lysosomal degradation of Rhodopsin and TRP and retinal degeneration in wild-type photoreceptors. Our results suggest that sphingosine kinases and their metabolites modulate photoreceptor homeostasis by influencing endolysosomal trafficking of Rhodopsin and TRP.

Abbreviations: DHS, dihydrosphingosine • DHS1P, DHS 1 phosphate • GMR, glass multimer reporter • GPCR, G protein–coupled receptor • IPP, inositol polyphosphate 1 phosphatase • Rh1, Rhodopsin 1 • S1P, sphingosine 1 phosphate • TRP, transient receptor potential • UAS, upstream activating sequence • UFLC MS/MS, ultrafast liquid chromatography coupled to tandem mass spectrometry

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