MPI of Molecular Cell Biology and Genetics, Dresden, Germany.
Department of Chemistry, Technische Universität Dresden, Dresden, Germany.
Nat Chem Biol. 2017 Jun;13(6):647-654. doi: 10.1038/nchembio.2347. Epub 2017 Apr 3.
The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is indispensable. Here, we present a novel class of C. elegans phosphorylated glycosphingolipids, phosphoethanolamine glucosylceramides (PEGCs), capable of rescuing larval arrest induced by sterol starvation. We describe the total synthesis of a major PEGC species and demonstrate that the PEGC synthetic counterpart suppresses the dauer-constitutive phenotype of Niemann-Pick C1 (NPC1) and DAF-7/TGF-β mutant worms caused by impaired intracellular sterol trafficking. PEGC biosynthesis depends on functional NPC1 and TGF-β, indicating that these proteins control larval development at least partly through PEGC. Furthermore, glucosylceramide deficiency dramatically reduced PEGC amounts. However, the resulting developmental arrest could be rescued by oversaturation of food with cholesterol. Taken together, these data show that PEGC is essential for C. elegans development through its regulation of sterol mobilization.
秀丽隐杆线虫需要外源性胆固醇才能存活，其耗竭会导致早期发育停滞。因此，严格调控胆固醇在生物体中的储存和分布是必不可少的。在这里，我们提出了一类秀丽隐杆线虫新型磷酸化糖脂，即磷酸乙醇胺葡糖神经酰胺（PEGCs），它们能够挽救由固醇饥饿引起的幼虫停滞。我们描述了一种主要 PEGC 物种的全合成，并证明 PEGC 合成类似物抑制了因细胞内固醇运输受损而导致的尼曼-匹克 C1（NPC1）和 DAF-7/TGF-β突变体线虫 dauer 组成型表型。PEGC 生物合成依赖于功能性 NPC1 和 TGF-β，表明这些蛋白至少部分通过 PEGC 控制幼虫发育。此外，葡糖神经酰胺缺乏会显著减少 PEGC 的数量。然而，通过用胆固醇过度饱和食物可以挽救由此导致的发育停滞。综上所述，这些数据表明，通过调节固醇动员，PEGC 对秀丽隐杆线虫的发育是必不可少的。
