The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth, metabolism and autophagy. Multiple pathways modulate mTORC1 in response to nutrients. Here we describe that nucleus–cytoplasmic shuttling of p300/EP300 regulates mTORC1 activity in response to amino acid or glucose levels. Depletion of these nutrients causes cytoplasm-to-nucleus relocalization of p300 that decreases acetylation of the mTORC1 component raptor, thereby reducing mTORC1 activity and activating autophagy. This is mediated by AMP-activated protein kinase-dependent phosphorylation of p300 at serine 89. Nutrient addition to starved cells results in protein phosphatase 2A-dependent dephosphorylation of nuclear p300, enabling its CRM1-dependent export to the cytoplasm to mediate mTORC1 reactivation. p300 shuttling regulates mTORC1 in most cell types and occurs in response to altered nutrients in diverse mouse tissues. Interestingly, p300 cytoplasm–nucleus shuttling is altered in cells from patients with Hutchinson–Gilford progeria syndrome. p300 mislocalization by the disease-causing protein, progerin, activates mTORC1 and inhibits autophagy, phenotypes that are normalized by modulating p300 shuttling. These results reveal how nutrients regulate mTORC1, a cytoplasmic complex, by shuttling its positive regulator p300 in and out of the nucleus, and how this pathway is misregulated in Hutchinson–Gilford progeria syndrome, causing mTORC1 hyperactivation and defective autophagy.

雷帕霉素复合物 1 (mTORC1) 的机制靶标是细胞生长、代谢和自噬的主要调节因子。多种途径调节 mTORC1 以响应营养物质。在这里，我们描述了 p300/EP300 的核-细胞质穿梭响应氨基酸或葡萄糖水平来调节 mTORC1 活性。这些营养物质的消耗会导致 p300 从细胞质到细胞核的重新定位，从而降低 mTORC1 组分猛禽的乙酰化，从而降低 mTORC1 活性并激活自噬。这是由 p300 在丝氨酸 89 处的 AMP 激活的蛋白激酶依赖性磷酸化介导的。向饥饿细胞添加营养物会导致核 p300 的蛋白磷酸酶 2A 依赖性去磷酸化，使其能够依赖 CRM1 输出到细胞质，从而介导 mTORC1 重新激活。p300 穿梭在大多数细胞类型中调节 mTORC1，并响应不同小鼠组织中营养物质的变化而发生。有趣的是，哈钦森-吉尔福德早衰综合征患者的细胞中 p300 细胞质-细胞核穿梭发生了改变。致病蛋白早老素导致 p300 错误定位，激活 mTORC1 并抑制自噬，通过调节 p300 穿梭使表型正常化。这些结果揭示了营养物质如何通过将其正调节因子 p300 进出细胞核来调节 mTORC1（一种细胞质复合物），以及该通路如何在 Hutchinson-Gilford 早衰综合征中被错误调节，导致 mTORC1 过度激活和自噬缺陷。