mTORC1 Phosphorylates Acetyltransferase p300 to Regulate Autophagy and Lipogenesis
mTORC1 Phosphorylates Acetyltransferase p300 to Regulate Autophagy and Lipogenesis
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mTORC1 磷酸化乙酰转移酶 p300 调节自噬和脂肪生成
DOI：
10.1016/j.molcel.2017.09.020
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发表时间：
2017-10-19
期刊：
影响因子：
16
通讯作者：
Liu, Wei
中科院分区：
文献类型：
--
作者：
Wan, Wei;You, Zhiyuan;Liu, Wei
乙酰化被越来越多地认为是哺乳动物细胞中多种细胞功能调节的主要翻译后机制之一。乙酰转移酶p300是一种乙酰化组蛋白和非组蛋白的酶，它在细胞生长和代谢中的作用已被广泛研究。然而，p300在细胞中激活的机制在很大程度上仍然未知。在这里，我们确定的稳态传感器mTORC 1作为p300的直接激活剂。活化的mTORC 1与p300相互作用，并在C-末端结构域的4个丝氨酸残基处磷酸化p300。从机制上讲，mTORC 1对p300的磷酸化阻止了催化HAT结构域与RING结构域的结合，从而消除了分子内抑制。在功能上，mTORC 1依赖的p300磷酸化抑制细胞饥饿诱导的自噬并激活细胞脂肪生成。这些结果揭示了p300作为mTORC 1的直接靶点，并表明mTORC 1 p300通路通过协调控制细胞凋亡和细胞增殖在细胞代谢中起着关键作用。
Acetylation is increasingly recognized as one of the major post-translational mechanisms for the regulation of multiple cellular functions in mammalian cells. Acetyltransferase p300, which acetylates histone and non-histone proteins, has been intensively studied in its role in cell growth and metabolism. However, the mechanism underlying the activation of p300 in cells remains largely unknown. Here, we identify the homeostatic sensor mTORC1 as a direct activator of p300. Activated mTORC1 interacts with p300 and phosphorylates p300 at 4 serine residues in the C-terminal domain. Mechanistically, phosphorylation of p300 by mTORC1 prevents the catalytic HAT domain from binding to the RING domain, thereby eliminating intra-molecular inhibition. Functionally, mTORC1dependent phosphorylation of p300 suppresses cellstarvation-induced autophagy and activates cell lipogenesis. These results uncover p300 as a direct target of mTORC1 and suggest that the mTORC1p300 pathway plays a pivotal role in cell metabolism by coordinately controlling cell anabolism and catabolism.