PDF(Pubmed)
Abstract：
The pathological accumulation of cholesterol is a signature feature of Niemann-Pick type C (NPC) disease, in which excessive lipid levels induce Purkinje cell death in the cerebellum. NPC1 encodes a lysosomal cholesterol-binding protein, and mutations in NPC1 drive cholesterol accumulation in late endosomes and lysosomes (LE/Ls). However, the fundamental role of NPC proteins in LE/L cholesterol transport remains unclear. Here, we demonstrate that NPC1 mutations impair the projection of cholesterol-containing membrane tubules from the surface of LE/Ls. A proteomic survey of purified LE/Ls identified StARD9 as a novel lysosomal kinesin responsible for LE/L tubulation. StARD9 contains an N-terminal kinesin domain, a C-terminal StART domain, and a dileucine signal shared with other lysosome-associated membrane proteins. Depletion of StARD9 disrupts LE/L tubulation, paralyzes bidirectional LE/L motility and induces accumulation of cholesterol in LE/Ls. Finally, a novel StARD9 knock-out mouse recapitulates the progressive loss of Purkinje cells in the cerebellum. Together, these studies identify StARD9 as a microtubule motor protein responsible for LE/L tubulation and provide support for a novel model of LE/L cholesterol transport that becomes impaired in NPC disease.
摘要：
胆固醇的病理积累是Niemann-PickC型（NPC）疾病的特征，其中过度的脂质水平诱导小脑中的浦肯野细胞死亡。NPC1编码溶酶体胆固醇结合蛋白，NPC1中的突变驱动晚期内体和溶酶体(LE/Ls)中的胆固醇积累。然而,NPC蛋白在LE/L胆固醇转运中的基本作用尚不清楚.这里,我们证明NPC1突变会损害含胆固醇的膜小管从LE/Ls表面的投射。对纯化的LE/L的蛋白质组学调查确定StARD9是负责LE/L插管的新型溶酶体驱动蛋白。StARD9包含一个N末端驱动蛋白结构域，C端StART域，和与其他溶酶体相关的膜蛋白共享的二亮氨酸信号。StARD9的耗尽破坏了LE/L插管,麻痹双向LE/L运动并诱导LE/L中胆固醇的积累。最后,新型StARD9敲除小鼠概括了小脑中Purkinje细胞的进行性丧失。一起,这些研究将StARD9确定为负责LE/L插管的微管运动蛋白,并为在NPC疾病中受损的新型LE/L胆固醇转运模型提供支持.
