Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390-9039, USA.
Cell. 2011 Jan 21;144(2):253-67. doi: 10.1016/j.cell.2010.12.018.
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.
哺乳动物细胞中巨自噬的研究描述了诱导、囊泡成核和膜延伸复合物作为关键信号中间物，驱动自噬体生物发生。这些组件如何被招募到新形成的自噬体中尚不清楚，尽管人们已经了解了许多抑制自噬的信号机制，但能够促进自噬的正向诱导信号的性质仍然是未知的。我们发现 Ras 样小 G 蛋白 RalB 定位于新形成的自噬体上，并在营养剥夺时被激活。RalB 和其效应因子 Exo84 是营养饥饿诱导的自噬所必需的，而 RalB 的激活足以促进自噬体的形成。通过与 Exo84 的直接结合，RalB 诱导 ULK1 和 Beclin1-VPS34 复合物在胞外体上形成具有催化活性的复合物，这对于隔离膜的形成和成熟是必需的。因此，RalB 信号是对营养限制的主要适应性反应，通过动员核心囊泡成核机制直接参与自噬作用。
