Article abstract
Nature Cell Biology 10, 776 - 787 (2008)
Published online: 15 June 2008 | doi:10.1038/ncb1740
Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking
Chengyu Liang1,2, Jong-soo Lee1,2, Kyung-Soo Inn1,2, Michaela U. Gack1,2, Qinglin Li2, Esteban A. Roberts3, Isabelle Vergne3, Vojo Deretic3, Pinghui Feng4, Chihiro Akazawa5 & Jae U. Jung1,2
Abstract
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.
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.
- Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, 1 Pine Hill Drive, Southborough, MA 01772, USA.
- Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA.
- University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.
- Department of Biophysics and Biochemistry, Graduate School of Health Sciences, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-Ku, Tokyo 113-8519, Japan.
Correspondence to: Jae U. Jung1,2 e-mail: jaeujung@usc.edu
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