Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L
Late endosomal transport and tethering are coupled processes controlled by RILP and the cholesterol sensor ORP1L
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DOI：
10.1242/jcs.129270
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发表时间：
2013-08-01
影响因子：
4
通讯作者：
Neefjes, Jacques
中科院分区：
文献类型：
--
作者：
van der Kant, Rik;Fish, Alexander;Neefjes, Jacques
晚期内体和溶酶体是动态细胞器，它们不断移动和融合以从早期内体、吞噬体和自噬体获取物质。溶酶体动力学缺陷会导致严重的神经退行性疾病和发育疾病，例如尼曼-皮克 C 型疾病和 ARC 综合征，但人们对哺乳动物系统中晚期内体融合的调节知之甚少。用于融合的哺乳动物内体需要经过很长的距离运输才能开始接触。在这里，我们描述了溶酶体束缚和运输是由一种多蛋白复合物共同调节的组合过程：RAB7-RILP-ORP1L。我们证明 RILP 直接并同时结合束缚 HOPS 复合物和动力蛋白马达的 p150（胶合）亚基。 ORP1L 然后充当胆固醇感应开关，控制 RILP-HOPS-p150(Glued) 相互作用。我们证明 RILP 和 ORP1L 控制埃博拉病毒感染，这是一个依赖于晚期内体融合的过程。通过将动力蛋白马达和 HOPS 复合物的募集和调节结合到单个多蛋白复合物中，RAB7-RILP-ORP1L 复合物有效地耦合和调节微管负端运输和融合的时间，这是内体生物学中的两个主要事件。
Late endosomes and lysosomes are dynamic organelles that constantly move and fuse to acquire cargo from early endosomes, phagosomes and autophagosome. Defects in lysosomal dynamics cause severe neurodegenerative and developmental diseases, such as Niemann-Pick type C disease and ARC syndrome, yet little is known about the regulation of late endosomal fusion in a mammalian system. Mammalian endosomes destined for fusion need to be transported over very long distances before they tether to initiate contact. Here, we describe that lysosomal tethering and transport are combined processes co-regulated by one multi-protein complex: RAB7-RILP-ORP1L. We show that RILP directly and concomitantly binds the tethering HOPS complex and the p150(Glued) subunit of the dynein motor. ORP1L then functions as a cholesterol-sensing switch controlling RILP-HOPS-p150(Glued) interactions. We show that RILP and ORP1L control Ebola virus infection, a process dependent on late endosomal fusion. By combining recruitment and regulation of both the dynein motor and HOPS complex into a single multiprotein complex, the RAB7-RILP-ORP1L complex efficiently couples and regulates the timing of microtubule minus-end transport and fusion, two major events in endosomal biology.