英国剑桥大学David C. Rubinsztein研究组发现，p300核胞质穿梭是Hutchinson-Gilford早衰综合征中mTORC1过度激活的基础。相关论文于2024年1月24日在线发表在《自然—细胞生物学》杂志上。

研究人员描述了p300/EP300在细胞核-细胞质间的穿梭调节雷帕霉素机械靶点复合体1（mTORC1）的活性，以应对氨基酸或葡萄糖水平的变化。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成分raptor的乙酰化，进而降低mTORC1的活性并激活自噬。这是由AMP激活的蛋白激酶依赖p300在第89位丝氨酸处的磷酸化介导的。向饥饿细胞中添加营养物质会导致依赖蛋白磷酸酶2A的核p300去磷酸化，使其能够依赖CRM1输出到细胞质中，从而介导mTORC1的重新激活。

有趣的是，在Hutchinson-Gilford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。致病蛋白早衰素导致的p300错误定位激活了mTORC1并抑制了自噬，而这些表型通过调节p300穿梭可以恢复正常。

这些结果揭示了营养物质是如何通过使其正调控因子p300穿梭于细胞核内外来调控mTORC1（一种细胞质复合体）的，以及这一途径是如何在Hutchinson-Gilford早衰综合征中被误调，从而导致mTORC1过度激活和自噬缺陷的。

据了解，mTORC1是细胞生长、新陈代谢和自噬的主要调节因子。多种途径可调节mTORC1对营养物质的反应。

附：英文原文

Title: p300 nucleocytoplasmic shuttling underlies mTORC1 hyperactivation in Hutchinson–Gilford progeria syndrome

Author: Son, Sung Min, Park, So Jung, Breusegem, Sophia Y., Larrieu, Delphine, Rubinsztein, David C.

Issue&Volume: 2024-01-24

Abstract: 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.

DOI: 10.1038/s41556-023-01338-y

Source: https://www.nature.com/articles/s41556-023-01338-y