Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism
Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism
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Pacer 是 mTORC1 和 GSK3-TIP60 信号传导调节自噬体成熟和脂质代谢的介质
DOI：
10.1016/j.molcel.2018.12.017
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发表时间：
2019-02-21
期刊：
影响因子：
16
通讯作者：
Sun, Qiming
中科院分区：
文献类型：
--
作者：
Cheng, Xiawei;Ma, Xiuling;Sun, Qiming
MTORC1和GSK3在(宏观)自噬的早期阶段起着关键作用，但它们如何调控自噬的后期步骤仍然知之甚少。在这里，我们展示了mTORC1和GSK3-Tip60信号的融合，通过我们最近的研究中发现的一种自噬调节因子Pacer来调节自噬小体的成熟。在小鼠中，肝细胞特异性的起搏基因敲除会导致自噬通量、糖原和脂肪积累受损，以及肝纤维化。在营养丰富的条件下，mTORC1在丝氨酸157处磷酸化步行者，破坏步行者与Stx17和啤酒花复合体的联系，从而取消步行者介导的自噬小体成熟。重要的是，在缺乏营养的条件下，起搏器的去磷酸化促进了Tip60介导的起搏器乙酰化，这促进了啤酒花复合体的招募，是自噬体成熟和脂滴清除所必需的。这项工作不仅证实了步行者是体内肝脏自噬和肝脏动态平衡的调节者，而且揭示了参与自噬和脂质代谢后期阶段的信号整合机制。
mTORC1 and GSK3 play critical roles in early stages of (macro)autophagy, but how they regulate late steps of autophagy remains poorly understood. Here we show that mTORC1 and GSK3-TIP60 signaling converge to modulate autophagosome maturation through Pacer, an autophagy regulator that was identified in our recent study. Hepatocyte-specific Pacer knockout in mice results in impaired autophagy flux, glycogen and lipid accumulation, and liver fibrosis. Under nutrient-rich conditions, mTORC1 phosphorylates Pacer at serine157 to disrupt the association of Pacer with Stx17 and the HOPS complex and thus abolishes Pacer-mediated autophagosome maturation. Importantly, dephosphorylation of Pacer under nutrient-deprived conditions promotes TIP60-mediated Pacer acetylation, which facilitates HOPS complex recruitment and is required for autophagosome maturation and lipid droplet clearance. This work not only identifies Pacer as a regulator in hepatic autophagy and liver homeostasis in vivo but also reveals a signal integration mechanism involved in late stages of autophagy and lipid metabolism.