Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking
Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking
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DOI：
10.1038/ncb1740
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发表时间：
2008-07-01
影响因子：
21.3
通讯作者：
Jung, Jae U.
中科院分区：
文献类型：
--
作者：
Liang, Chengyu;Lee, Jong-Soo;Jung, Jae U.
自噬和内吞途径是严格调控的膜重排过程，对于体内平衡、发育和疾病至关重要。自噬货物从自噬体传递到溶酶体，通过拓扑类似于内体成熟的复杂过程进行降解。在此，我们报道了 Beclin1 结合自噬肿瘤抑制因子 UVRAG 与 C 类 Vps 复合物（内体融合机制的关键组成部分）相互作用。这种相互作用刺激 Rab7 GTPase 活性以及自噬体与晚期内涵体/溶酶体的融合，从而增强自噬货物的递送和降解。此外，UVRAG-class-C-Vps 复合物加速内体-内体融合，导致内吞货物快速降解。值得注意的是，UVRAG-class-C-Vps 复合物介导的自噬体/内体成熟在遗传上与 UVRAG-Beclin1 介导的自噬体形成是可分离的。这一结果表明，UVRAG 作为一种多价运输效应子，不仅调节自噬自噬体形成和成熟的两个重要步骤，而且还调节内体融合，同时促进自噬和内吞货物向降解室的运输。
Autophagic and endocytic pathways are tightly regulated membrane rearrangement processes that are crucial for homeostasis, development and disease. Autophagic cargo is delivered from autophagosomes to lysosomes for degradation through a complex process that topologically resembles endosomal maturation. Here, we report that a Beclin1-binding autophagic tumour suppressor, UVRAG, interacts with the class C Vps complex, a key component of the endosomal fusion machinery. This interaction stimulates Rab7 GTPase activity and autophagosome fusion with late endosomes/lysosomes, thereby enhancing delivery and degradation of autophagic cargo. Furthermore, the UVRAG-class-C-Vps complex accelerates endosome-endosome fusion, resulting in rapid degradation of endocytic cargo. Remarkably, autophagosome/endosome maturation mediated by the UVRAG-class-C-Vps complex is genetically separable from UVRAG-Beclin1-mediated autophagosome formation. This result indicates that UVRAG functions as a multivalent trafficking effector that regulates not only two important steps of autophagy autophagosome formation and maturation-but also endosomal fusion, which concomitantly promotes transport of autophagic and endocytic cargo to the degradative compartments.