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J. Biol. Chem., Vol. 279, Issue 34, 35995-36002, August 20, 2004

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Drosophila Glucosylceramide Synthase

A NEGATIVE REGULATOR OF CELL DEATH MEDIATED BY PROAPOPTOTIC FACTORS^*

Ayako Kohyama-Koganeya, Takeshi Sasamura, Eriko Oshima, Emiko Suzuki¶, Shoko Nishihara||**, Ryu Ueda**, and Yoshio Hirabayashi

From the Neuronal Circuit Mechanisms Research Group, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), Wako-shi, Saitama 351-0198, Japan, the Department of Biological Science and Technology, Tokyo University of Science and the ^¶Department of Fine Morphology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108, Japan, the ^||Laboratory of Cell Biology, Department of Bioinformatics, Faculty of Engineering, Soka University, Hachioji, Tokyo, 192-8577, Japan, the Invertebrate Genetics Laboratory, National Institute of Genetics, Mishima, Shizuoka 441-8540, Japan, and the ^**Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST), Kawaguchi, Saitama 332-0012, Japan

Glucosylceramide synthase (GlcT-1) catalyzes the formation of glucosylceramide (GlcCer), the core structure of major glycosphingolipids (GSLs), from ceramide and UDP-glucose. Ceramide and its metabolites, such as sphingosine-1-phosphate, are now known to be important mediators of apoptosis and cell survival. Recently, we have shown that GlcT-1 functions to regulate intracellular ceramide levels via glycosylation of ceramide. In this study, we employ the fruit fly Drosophila melanogaster as a model system for understanding the in vivo roles of GlcT-1. We isolated and characterized a GlcT-1 homologue (DGlcT-1) from Drosophila. When DGlcT-1 was expressed in GM-95 cells deficient in GSLs (because of the absence of GlcT-1 activity), these cells regained the ability to synthesize GSLs. Northern blot and in situ hybridization analyses revealed that the expression of DGlcT-1 mRNA was ubiquitous throughout development, suggesting that DGlcT-1 is important for development and differentiation. Indeed, RNA interference experiments demonstrated that the loss of GlcT-1 function enhances apoptotic cell death. Conversely, targeted expression of GlcT-1 partially rescued cell death caused by the proapoptotic factors Reaper and Grim, suggesting that ceramide generation might be one signal pathway that executes the cell death program. We also found that GlcT-1 localized not only in the Golgi apparatus but also in the perinuclear endoplasmic reticulum, providing the first visual evidence of GlcT-1 in membranes. These results indicate that GlcT-1 might down-regulate ceramide generated in these membranes.

Received for publication, January 15, 2004 , and in revised form, May 24, 2004.

^* This work was supported by Grant-in-aid 12140201 (Scientific Research on Priority Areas (B) (to Y. H.) from the Ministry of Education, Culture, Sports, Science and Technology) and the Brain Science Institute and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Corporation (JST) (to Y. H., R. U., and S. N., respectively). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Neuronal Circuit Mechanisms Research Group, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel./Fax: 81-48-467-6372; E-mail: hirabaya{at}postman.riken.jp.

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