Zhang M, Dwyer N K, Love D C, Cooney A, Comly M, Neufeld E, Pentchev P G, Blanchette-Mackie E J, Hanover J A
Lipid Cell Biology Section and Cell Biochemistry Section, National Institute of Diabetes and Digestive and Kidney Diseases, and Developmental and Metabolic Neurology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4466-71. doi: 10.1073/pnas.081070898.
Niemann-Pick type C1 (NPC1) disease results from a defect in the NPC1 protein and is characterized by a pathological accumulation of cholesterol and glycolipids in endocytic organelles. We followed the biosynthesis and trafficking of NPC1 with the use of a functional green fluorescent protein-fused NPC1. Newly synthesized NPC1 is exported from the endoplasmic reticulum and requires transit through the Golgi before it is targeted to late endosomes. NPC1-containing late endosomes then move by a dynamic process involving tubulation and fission, followed by rapid retrograde and anterograde migration along microtubules. Cell fusion studies with normal and mutant NPC1 cells show that exchange of contents between late endosomes and lysosomes depends upon ongoing tubulovesicular late endocytic trafficking. In turn, rapid endosomal tubular movement requires an intact NPC1 sterol-sensing domain and is retarded by an elevated endosomal cholesterol content. We conclude that the neuropathology and cellular lysosomal lipid accumulation in NPC1 disease results, at least in part, from striking defects in late endosomal tubulovesicular trafficking.
尼曼-匹克C1型（NPC1）病是由NPC1蛋白缺陷引起的，其特征是胆固醇和糖脂在内吞细胞器中病理性蓄积。我们利用功能性绿色荧光蛋白融合的NPC1追踪了NPC1的生物合成和运输过程。新合成的NPC1从内质网输出，在靶向晚期内体之前需要经过高尔基体。含有NPC1的晚期内体随后通过一个涉及微管形成和裂变的动态过程移动，接着沿着微管进行快速逆行和顺行迁移。正常细胞与突变型NPC1细胞的细胞融合研究表明，晚期内体与溶酶体之间的内容物交换取决于正在进行的微管泡状晚期内吞运输。反过来，晚期内体的快速微管移动需要完整的NPC1固醇感应结构域，并且会因晚期内体胆固醇含量升高而受到阻碍。我们得出结论，NPC1病中的神经病理学和细胞溶酶体脂质蓄积至少部分是由晚期内体微管泡状运输的显著缺陷导致的。
