Filipek Przemyslaw A, de Araujo Mariana E G, Vogel Georg F, De Smet Cedric H, Eberharter Daniela, Rebsamen Manuele, Rudashevskaya Elena L, Kremser Leopold, Yordanov Teodor, Tschaikner Philipp, Fürnrohr Barbara G, Lechner Stefan, Dunzendorfer-Matt Theresia, Scheffzek Klaus, Bennett Keiryn L, Superti-Furga Giulio, Lindner Herbert H, Stasyk Taras, Huber Lukas A
Division of Cell Biology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
Department of Pediatrics I, Innsbruck Medical University, Innsbruck, Austria.
J Cell Biol. 2017 Dec 4;216(12):4199-4215. doi: 10.1083/jcb.201703061. Epub 2017 Oct 9.
Signaling from lysosomes controls cellular clearance and energy metabolism. Lysosomal malfunction has been implicated in several pathologies, including neurodegeneration, cancer, infection, immunodeficiency, and obesity. Interestingly, many functions are dependent on the organelle position. Lysosomal motility requires the integration of extracellular and intracellular signals that converge on a competition between motor proteins that ultimately control lysosomal movement on microtubules. Here, we identify a novel upstream control mechanism of Arl8b-dependent lysosomal movement toward the periphery of the cell. We show that the C-terminal domain of lyspersin, a subunit of BLOC-1-related complex (BORC), is essential and sufficient for BORC-dependent recruitment of Arl8b to lysosomes. In addition, we establish lyspersin as the linker between BORC and late endosomal/lysosomal adaptor and mitogen activated protein kinase and mechanistic target of rapamycin activator (LAMTOR) complexes and show that epidermal growth factor stimulation decreases LAMTOR/BORC association, thereby promoting BORC- and Arl8b-dependent lysosomal centrifugal transport.
来自溶酶体的信号传导控制着细胞清除和能量代谢。溶酶体功能异常与多种疾病有关，包括神经退行性变、癌症、感染、免疫缺陷和肥胖。有趣的是，许多功能取决于细胞器的位置。溶酶体运动需要整合细胞外和细胞内信号，这些信号汇聚在驱动蛋白之间的竞争上，最终控制溶酶体在微管上的移动。在这里，我们确定了一种新的上游控制机制，该机制可使依赖Arl8b的溶酶体向细胞周边移动。我们表明，溶酶体素（一种与BLOC-1相关复合物（BORC）的亚基）的C末端结构域对于BORC依赖的Arl8b募集到溶酶体是必不可少且足够的。此外，我们确定溶酶体素是BORC与晚期内体/溶酶体衔接蛋白以及丝裂原活化蛋白激酶和雷帕霉素作用靶点复合物（LAMTOR）之间的连接物，并表明表皮生长因子刺激会降低LAMTOR/BORC的结合，从而促进依赖BORC和Arl8b的溶酶体离心运输。
