Department of Biochemistry, and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
National Institute of Biological Sciences, Beijing 102206, China.
Mol Cell. 2019 Feb 21;73(4):788-802.e7. doi: 10.1016/j.molcel.2018.12.017. Epub 2019 Jan 28.
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.
mTORC1 和 GSK3 在（大）自噬的早期阶段发挥关键作用，但它们如何调节自噬的后期步骤仍知之甚少。在这里，我们表明 mTORC1 和 GSK3-TIP60 信号通过 Pacer 来调节自噬体成熟，Pacer 是我们最近的研究中发现的一种自噬调节剂。在小鼠中，肝细胞特异性敲除 Pacer 会导致自噬流受损、糖原和脂质积累以及肝纤维化。在营养丰富的条件下，mTORC1 磷酸化 Pacer 的丝氨酸 157 以破坏 Pacer 与 Stx17 和 HOPS 复合物的结合，从而阻止 Pacer 介导的自噬体成熟。重要的是，在营养剥夺条件下 Pacer 的去磷酸化促进了 TIP60 介导的 Pacer 乙酰化，这有助于 HOPS 复合物的募集，是自噬体成熟和脂滴清除所必需的。这项工作不仅鉴定了 Pacer 作为体内肝脏自噬和肝脏稳态的调节剂，还揭示了参与自噬和脂质代谢后期阶段的信号整合机制。
