Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking

被引:613
作者
Liang, Chengyu [1 ,2 ,3 ]
Lee, Jong-Soo [1 ,2 ,3 ]
Inn, Kyung-Soo [1 ,2 ,3 ]
Gack, Michaela U. [1 ,2 ,3 ]
Li, Qinglin [2 ,3 ]
Roberts, Esteban A. [4 ]
Vergne, Isabelle [4 ]
Deretic, Vojo [4 ]
Feng, Pinghui [5 ]
Akazawa, Chihiro [6 ]
Jung, Jae U. [1 ,2 ,3 ]
机构
[1] Univ So Calif, Dept Mol Microbiol & Immunol, Los Angeles, CA 90033 USA
[2] Harvard Univ, Sch Med, New England Primate Res Ctr, Dept Microbiol & Mol Genet, Southborough, MA 01772 USA
[3] Harvard Univ, Sch Med, New England Primate Res Ctr, Div Tumor Virol, Southborough, MA 01772 USA
[4] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA
[5] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA
[6] Tokyo Med & Dent Univ, Grad Sch Hlth Sci, Dept Biophys & Biochem, Bunkyo Ku, Tokyo 1138519, Japan
关键词
D O I
10.1038/ncb1740
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:776 / 787
页数:12
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