Université Côte d'Azur, Centre National de la Recherche Scientifique, Institut de Biologie Valrose, Nice-France.
Université Côte d'Azur, Institut national de la santé et de la recherche médicale, Institut de Biologie Valrose, Nice -France.
PLoS One. 2019 Feb 8;14(2):e0209759. doi: 10.1371/journal.pone.0209759. eCollection 2019.
Basal autophagy is as a compressive catabolic mechanism engaged in the breakdown of damaged macromolecules and organelles leading to the recycling of elementary nutrients. Thought essential to cellular refreshing, little is known about the origin of a constitutional rate of basal autophagy. Here, we found that loss of Drosophila vacuolar peduncle (vap), a presumed GAP enzyme, is associated with enhanced basal autophagy rate and physiological alterations resulting in a wasteful cell energy balance, a hallmark of overactive autophagy. By contrast, starvation-induced autophagy was disrupted in vap mutant conditions, leading to a block of maturation into autolysosomes. This phenotype stem for exacerbated biogenesis of PI(3)P-dependent endomembranes, including autophagosome membranes and ectopic fusions of vesicles. These findings shed new light on the neurodegenerative phenotype found associated to mutant vap adult brains in a former study. A partner of Vap, Sprint (Spri), acting as an endocytic GEF for Rab5, had the converse effect of leading to a reduction in PI(3)P-dependent endomembrane formation in mutants. Spri was conditional to normal basal autophagy and instrumental to the starvation-sensitivity phenotype specific of vap. Rab5 activity itself was essential for PI(3)P and for pre-autophagosome structures formation. We propose that Vap/Spri complexes promote a cell surface-derived flow of endocytic Rab5-containing vesicles, the traffic of which is crucial for the implementation of a basal autophagy rate.
基础自噬是一种压缩性的分解代谢机制，参与破坏受损的大分子和细胞器，导致基本营养物质的再循环。尽管基础自噬对于细胞更新至关重要，但对于基础自噬率的起源知之甚少。在这里，我们发现果蝇液泡小柄（vap）缺失，一种假定的 GAP 酶，与基础自噬率的增强以及导致浪费细胞能量平衡的生理变化有关，这是过度活跃自噬的一个标志。相比之下，在 vap 突变条件下，饥饿诱导的自噬被破坏，导致成熟为自溶酶体的过程受阻。这种表型源于 PI(3)P 依赖性内膜的过度生物发生，包括自噬体膜和囊泡的异位融合。这些发现为以前研究中发现与突变 vap 成年大脑相关的神经退行性表型提供了新的线索。Vap 的一个伙伴 Sprint（Spri），作为 Rab5 的内吞 GEF，其作用与导致突变体中 PI(3)P 依赖性内膜形成减少相反。Spri 对正常基础自噬有条件作用，并且对 vap 特有的饥饿敏感性表型至关重要。Rab5 活性本身对于 PI(3)P 和前自噬体结构的形成是必不可少的。我们提出，Vap/Spri 复合物促进含有内吞 Rab5 的囊泡从细胞表面流出，这种运输对于实施基础自噬率至关重要。
