Institute of Bioengineering and Nanotechnology, Agency for Science, Technology, and Research, Singapore.
Mol Biol Cell. 2010 Mar 1;21(5):778-90. doi: 10.1091/mbc.e09-01-0005. Epub 2010 Jan 6.
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.
在脂质贮积病中，由于胆固醇异常积聚，鞘脂的细胞内转运受到影响。最近，果蝇被用于模拟脂质贮积病，但固醇积累对果蝇鞘脂转运的影响尚不清楚，而且一般来说，在这个模式生物中尚未研究过鞘脂的转运。在这里，我们研究了荧光糖脂类似物 BODIPY-乳糖基神经酰胺在果蝇神经元中的摄取和细胞内分布。这种简单糖脂的摄取机制和细胞内转运途径在很大程度上是保守的。我们的主要发现是胆固醇指导糖脂在高尔基体、溶酶体和再循环隔室之间的转运。我们的分析支持这样的观点，即果蝇中的胆固醇储存引发了糖脂从生物合成到降解性内体途径的转运转换，而胆固醇耗竭则消除了糖脂的再循环。出乎意料的是，我们观察到一种我们称之为“劫持”的新现象，其中乳糖基神经酰胺完全改变了内吞货物葡聚糖的转运途径，使其远离溶酶体靶标。这项工作表明，果蝇中的糖脂转运在胆固醇储存条件下发生了类似于在哺乳动物细胞中观察到的变化，因此验证了果蝇是研究脂质贮积病的合适模式生物。
