Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking.
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.
Chengyu
C
Liang
Jong-soo
JS
Lee
Kyung-soo
KS
Inn
Michaela U
MU
Gack
Qinglin
Q
Li
Esteban A
EA
Roberts
Isabelle
I
Vergne
Vojo
V
Deretic
Pinghui
P
Feng
Chihiro
C
Akazawa
Jae U
JU
Jung
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology*; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008561:Membrane Fusion / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism*; D010588:Phagosomes / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; C408122:UVRAG protein, human; D033921:Vesicular Transport Proteins; D020691:rab GTP-Binding Proteins