Nutrient-dependent mTORC1 Association with the ULK1-Atg13-FIP200 Complex Required for Autophagy
Nutrient-dependent mTORC1 Association with the ULK1-Atg13-FIP200 Complex Required for Autophagy
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DOI：
10.1091/mbc.e08-12-1248
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发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Mizushima, Noboru
中科院分区：
文献类型：
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作者：
Hosokawa, Nao;Hara, Taichi;Mizushima, Noboru
自噬是一种细胞内的降解系统，通过它细胞质内容物在溶酶体中被降解。自噬是由营养耗尽动态诱导的，以提供细胞内必需的氨基酸，从而帮助它们适应饥饿。虽然已经表明mTOR是自噬的主要负调节因子，但它如何控制自噬尚未确定。在这里，我们报告了一种新的哺乳动物自噬因子，Atg 13，它与ULK 1和FIP 200形成稳定的类似于3-MDa的蛋白复合物。atg 13定位于自噬隔离膜上，并且对于自噬体形成是必需的。与酵母对应物相比，ULK 1-Atg 13-FIP 200复合物的形成不受营养条件的影响。重要的是，mTORC 1以营养依赖性方式通过ULK 1掺入ULK 1-Atg 13-FIP 200复合物中，mTOR使ULK 1和Atg 13磷酸化。ULK 1通过雷帕霉素处理或饥饿去磷酸化。这些数据表明，mTORC 1通过直接调节类似于3-MDa ULK 1-Atg 13-FIP 200复合物来抑制自噬。
Autophagy is an intracellular degradation system, by which cytoplasmic contents are degraded in lysosomes. Autophagy is dynamically induced by nutrient depletion to provide necessary amino acids within cells, thus helping them adapt to starvation. Although it has been suggested that mTOR is a major negative regulator of autophagy, how it controls autophagy has not yet been determined. Here, we report a novel mammalian autophagy factor, Atg13, which forms a stable similar to 3-MDa protein complex with ULK1 and FIP200. Atg13 localizes on the autophagic isolation membrane and is essential for autophagosome formation. In contrast to yeast counterparts, formation of the ULK1-Atg13-FIP200 complex is not altered by nutrient conditions. Importantly, mTORC1 is incorporated into the ULK1-Atg13-FIP200 complex through ULK1 in a nutrient-dependent manner and mTOR phosphorylates ULK1 and Atg13. ULK1 is dephosphorylated by rapamycin treatment or starvation. These data suggest that mTORC1 suppresses autophagy through direct regulation of the similar to 3-MDa ULK1-Atg13-FIP200 complex.