Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
Dev Cell. 2013 Dec 9;27(5):489-503. doi: 10.1016/j.devcel.2013.10.017. Epub 2013 Nov 21.
Autophagy is a highly conserved catabolic process that degrades and recycles intracellular components through the lysosomes. Atg9 is the only integral membrane protein among autophagy-related (Atg) proteins thought to carry the membrane source for forming autophagosomes. Here we show that Drosophila Atg9 interacts with Drosophila tumor necrosis factor receptor-associated factor 2 (dTRAF2) to regulate the c-Jun N-terminal kinase (JNK) signaling pathway. Significantly, depletion of Atg9 and dTRAF2 compromised JNK-mediated intestinal stem cell proliferation and autophagy induction upon bacterial infection and oxidative stress stimulation. In mammalian cells, mAtg9 interacts with TRAF6, the homolog of dTRAF2, and plays an essential role in regulating oxidative stress-induced JNK activation. Moreover, we found that ROS-induced autophagy acts as a negative feedback regulator of JNK activity by dissociating Atg9/mAtg9 from dTRAF2/TRAF6 in Drosophila and mammalian cells, respectively. Our findings indicate a dual role for Atg9 in the regulation of JNK signaling and autophagy under oxidative stress conditions.
自噬是一种高度保守的分解代谢过程，通过溶酶体降解和回收细胞内成分。Atg9 是自噬相关（Atg）蛋白中唯一的完整膜蛋白，被认为是形成自噬体的膜来源。在这里，我们表明果蝇 Atg9 与果蝇肿瘤坏死因子受体相关因子 2（dTRAF2）相互作用，以调节 c-Jun N 末端激酶（JNK）信号通路。重要的是，耗尽 Atg9 和 dTRAF2 会损害细菌感染和氧化应激刺激时 JNK 介导的肠干细胞增殖和自噬诱导。在哺乳动物细胞中，mAtg9 与 TRAF6（dTRAF2 的同源物）相互作用，在调节氧化应激诱导的 JNK 激活中发挥重要作用。此外，我们发现 ROS 诱导的自噬通过分别在果蝇和哺乳动物细胞中使 Atg9/mAtg9 与 dTRAF2/TRAF6 解离，作为 JNK 活性的负反馈调节剂。我们的研究结果表明，Atg9 在氧化应激条件下对 JNK 信号和自噬的调节具有双重作用。
