StARD9 is a novel lysosomal kinesin required for membrane tubulation, cholesterol transport and Purkinje cell survival
| Autor: | Felicity R. Sterling, Jon D'Amico, Alexandria M. Brumfield, Kara L. Huegel, Patricia S. Vaughan, Kathryn Morris, Shelby Schwarz, Michelle V. Joyce, Bill Boggess, Matthew M. Champion, Kevin Maciuba, Philip Allen, Eric Marasco, Grant Koch, Peter Gonzalez, Shannon Hodges, Shannon Leahy, Erica Gerstbauer, Edward H. Hinchcliffe, Kevin T. Vaughan |
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| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Journal of Cell Science. 136 |
| ISSN: | 1477-9137 0021-9533 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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