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, mTORC1-dependent phosphorylation of p300 suppresses cell-starvation-induced autophagy and activates cell lipogenesis. These results uncover p300 as a direct target of mTORC1 and suggest that the mTORC1-p300 pathway plays a pivotal role in cell metabolism by coordinately controlling cell anabolism and catabolism.

乙酰化日益被认为是调节哺乳动物细胞中多种细胞功能的主要翻译后机制之一。乙酰化组蛋白和非组蛋白的乙酰基转移酶p300，已在其在细胞生长和代谢中的作用进行了深入研究。但是，在细胞中激活p300的机制仍是未知之数。在这里，我们将稳态传感器mTORC1识别为p300的直接激活剂。激活的mTORC1与p300相互作用，并在C端结构域的4个丝氨酸残基上磷酸化p300。从机理上讲，mTORC1使p300磷酸化可防止HAT催化域与RING域结合，从而消除分子内抑制。在功能上 p300的mTORC1依赖性磷酸化抑制细胞饥饿诱导的自噬并激活细胞脂肪形成。这些结果揭示了p300作为mTORC1的直接靶标，并表明mTORC1-p300途径通过协调控制细胞的合成代谢和分解代谢在细胞代谢中发挥关键作用。