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Published online 22 October 2001. doi:10.1083/jcb.200106104
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© The Rockefeller University Press, 0021-9525/2001/10/369 $5.00
The Journal of Cell Biology, Volume 155, Number 3, October 29, 2001 369-380

Article

Glycosphingolipids are required for sorting melanosomal proteins in the Golgi complex



Hein Sprong1,2, Sophie Degroote1, Tijs Claessens2, Judith van Drunen2, Viola Oorschot2,3, Ben H.C. Westerink4, Yoshio Hirabayashi5, Judith Klumperman2,3, Peter van der Sluijs2 and Gerrit van Meer1

1 Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, 1100 DE, Amsterdam, Netherlands
2 Department of Cell Biology, University Medical Center, Institute of Biomembranes
3 Center for Biomedical Genetics, 3584 CX, Utrecht, Netherlands
4 Department of Medicinal Chemistry, Center for Pharmacy, University of Groningen, 9713 AV Groningen, Netherlands
5 Laboratory for Memory and Learning, RIKEN Brain Science Institute, Saitama 351-0198, Japan

Address correspondence to Gerrit van Meer, Dept. of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, Netherlands. Tel.: 31-20-566-4965. Fax: 31-20-697-4156. E-mail: g.vanmeer{at}amc.uva.nl

A;lthough glycosphingolipids are ubiquitously expressed and essential for multicellular organisms, surprisingly little is known about their intracellular functions. To explore the role of glycosphingolipids in membrane transport, we used the glycosphingolipid-deficient GM95 mouse melanoma cell line. We found that GM95 cells do not make melanin pigment because tyrosinase, the first and rate-limiting enzyme in melanin synthesis, was not targeted to melanosomes but accumulated in the Golgi complex. However, tyrosinase-related protein 1 still reached melanosomal structures via the plasma membrane instead of the direct pathway from the Golgi. Delivery of lysosomal enzymes from the Golgi complex to endosomes was normal, suggesting that this pathway is not affected by the absence of glycosphingolipids. Loss of pigmentation was due to tyrosinase mislocalization, since transfection of tyrosinase with an extended transmembrane domain, which bypassed the transport block, restored pigmentation. Transfection of ceramide glucosyltransferase or addition of glucosylsphingosine restored tyrosinase transport and pigmentation. We conclude that protein transport from Golgi to melanosomes via the direct pathway requires glycosphingolipids.

Key Words: glycosphingolipid; protein sorting; melanosome; tyrosinase; TRP-1


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