Department of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Department of Chemistry, University of Virginia, Charlottesville, VA 22904, USA.
Cell Rep. 2021 Jul 27;36(4):109451. doi: 10.1016/j.celrep.2021.109451.
Lipid droplets (LDs) are dynamic organelles that undergo dynamic changes in response to changing cellular conditions. During nutrient depletion, LD numbers increase to protect cells against toxic fatty acids generated through autophagy and provide fuel for beta-oxidation. However, the precise mechanisms through which these changes are regulated have remained unclear. Here, we show that the small GTPase RalA acts downstream of autophagy to directly facilitate LD growth during nutrient depletion. Mechanistically, RalA performs this function through phospholipase D1 (PLD1), an enzyme that converts phosphatidylcholine (PC) to phosphatidic acid (PA) and that is recruited to lysosomes during nutrient stress in a RalA-dependent fashion. RalA inhibition prevents recruitment of the LD-associated protein perilipin 3, which is required for LD growth. Our data support a model in which RalA recruits PLD1 to lysosomes during nutrient deprivation to promote the localized production of PA and the recruitment of perilipin 3 to expanding LDs.
脂滴（LDs）是一种动态细胞器，可根据细胞状态的变化发生动态改变。在营养缺乏时，LD 的数量会增加，以防止自噬产生的有毒脂肪酸，并为β-氧化提供燃料。然而，这些变化是如何被调节的具体机制仍不清楚。在这里，我们表明小 GTPase RalA 在自噬的下游作用，直接促进营养缺乏时 LD 的生长。从机制上讲，RalA 通过磷脂酶 D1（PLD1）发挥此功能，PLD1 将磷脂酰胆碱（PC）转化为磷脂酸（PA），并在营养胁迫下以 RalA 依赖的方式被招募到溶酶体中。RalA 抑制阻止了与 LD 相关的蛋白 perilipin 3 的募集，perilipin 3 是 LD 生长所必需的。我们的数据支持这样一种模型，即在营养剥夺期间，RalA 将 PLD1 招募到溶酶体中，以促进局部 PA 的产生和 perilipin 3 向扩展的 LD 的募集。
