Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
UK Dementia Research Institute, Cambridge Institute for Medical Research (CIMR), University of Cambridge, Cambridge, UK.
Nat Commun. 2020 Jun 19;11(1):3148. doi: 10.1038/s41467-020-16886-2.
Macroautophagy ("autophagy") is the main lysosomal catabolic process that becomes activated under nutrient-depleted conditions, like amino acid (AA) starvation. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-conserved negative regulator of autophagy. While leucine (Leu) is a critical mTORC1 regulator under AA-starved conditions, how Leu regulates autophagy is poorly understood. Here, we describe that in most cell types, including neurons, Leu negatively regulates autophagosome biogenesis via its metabolite, acetyl-coenzyme A (AcCoA). AcCoA inhibits autophagy by enhancing EP300-dependent acetylation of the mTORC1 component raptor, with consequent activation of mTORC1. Interestingly, in Leu deprivation conditions, the dominant effects on autophagy are mediated by decreased raptor acetylation causing mTORC1 inhibition, rather than by altered acetylation of other autophagy regulators. Thus, in most cell types we examined, Leu regulates autophagy via the impact of its metabolite AcCoA on mTORC1, suggesting that AcCoA and EP300 play pivotal roles in cell anabolism and catabolism.
自噬（“autophagy”）是溶酶体主要的分解代谢过程，在营养缺乏条件下（如氨基酸饥饿）被激活。雷帕霉素复合物 1（mTORC1）是自噬的一个保守的负调控因子。亮氨酸（Leu）在氨基酸饥饿条件下是 mTORC1 的关键调控因子，但亮氨酸如何调节自噬尚不清楚。在这里，我们描述了在包括神经元在内的大多数细胞类型中，亮氨酸通过其代谢物乙酰辅酶 A（AcCoA）负调控自噬体生物发生。AcCoA 通过增强 mTORC1 成分 raptor 的 EP300 依赖性乙酰化，从而激活 mTORC1，来抑制自噬。有趣的是，在亮氨酸缺乏条件下，对自噬的主要影响是通过降低 raptor 乙酰化导致 mTORC1 抑制，而不是通过改变其他自噬调节剂的乙酰化。因此，在我们研究的大多数细胞类型中，亮氨酸通过其代谢物 AcCoA 对 mTORC1 的影响来调节自噬，这表明 AcCoA 和 EP300 在细胞合成代谢和分解代谢中发挥关键作用。
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