RalB and the Exocyst Mediate the Cellular Starvation Response by Direct Activation of Autophagosome Assembly

SummaryThe 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (308 K)Download as PowerPoint slideHighlights► RalB activation is a proximal signal to the promotion of autophagy ► The exocyst is a RalB effector required for nutrient deprivation-induced autophagy ► Exo84 and Sec5 are positive and negative regulatory partners for Beclin1 and ULK1 ► RalB binding induces Exo84-dependent ULK1 activation and autophagosome biogenesis