RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly |
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Authors: | Bodemann Brian O Orvedahl Anthony Cheng Tzuling Ram Rosalyn R Ou Yi-Hung Formstecher Etienne Maiti Mekhala Hazelett C Clayton Wauson Eric M Balakireva Maria Camonis Jacques H Yeaman Charles Levine Beth White Michael A |
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Affiliation: | 1 Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390-9039, USA 2 Department of Internal Medicine and Microbiology and Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390-9039, USA 3 Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390-9039, USA 4 Hybrigenics, Inc., 75014 Paris, France 5 Department of Anatomy and Cell Biology, University of Iowa, Iowa City, IA 52242, USA 6 Institut Curie, Inserm U-548, 75248 Paris, France |
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Abstract: | The study of macroautophagy in mammalian cells has described induction, vesicle nucleation, and membrane elongation complexes as key signaling intermediates driving autophagosome biogenesis. How these components are recruited to nascent autophagosomes is poorly understood, and although much is known about signaling mechanisms that restrain autophagy, the nature of positive inductive signals that can promote autophagy remain cryptic. We find that the Ras-like small G protein, RalB, is localized to nascent autophagosomes and is activated on nutrient deprivation. RalB and its effector Exo84 are required for nutrient starvation-induced autophagocytosis, and RalB activation is sufficient to promote autophagosome formation. Through direct binding to Exo84, RalB induces the assembly of catalytically active ULK1 and Beclin1-VPS34 complexes on the exocyst, which are required for isolation membrane formation and maturation. Thus, RalB signaling is a primary adaptive response to nutrient limitation that directly engages autophagocytosis through mobilization of the core vesicle nucleation machinery. |
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