ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery
ULK-Atg13-FIP200 Complexes Mediate mTOR Signaling to the Autophagy Machinery
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DOI：
10.1091/mbc.e08-12-1249
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发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Kim, Do-Hyung
中科院分区：
文献类型：
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作者：
Jung, Chang Hwa;Jun, Chang Bong;Kim, Do-Hyung
自噬是饥饿诱导的大体积胞质组分的降解，当营养供应有限时，自噬在哺乳动物细胞中上调。尽管哺乳动物雷帕霉素靶蛋白（mTOR）被认为是自噬诱导的关键调节因子，但mTOR调节自噬的机制仍不清楚。在这里，我们确定mTOR磷酸化Atg 13的哺乳动物同源物和哺乳动物Atg 1同源物ULK 1和ULK 2。哺乳动物Atg 13结合ULK 1和ULK 2，并介导ULK蛋白与FIP 200的相互作用。Atg 13的结合稳定并激活ULK，并促进ULK对FIP 200的磷酸化，而Atg 13的敲低抑制自噬体的形成。雷帕霉素或亮氨酸剥夺（诱导自噬的条件）对mTOR的抑制导致ULK 1、ULK 2和Atg 13的去磷酸化，并激活ULK使FIP 200磷酸化。这些发现表明ULK-Atg 13-FIP 200复合物是mTOR的直接靶点，也是响应mTOR信号传导的自噬的重要调节剂。
Autophagy, the starvation-induced degradation of bulky cytosolic components, is up-regulated in mammalian cells when nutrient supplies are limited. Although mammalian target of rapamycin (mTOR) is known as the key regulator of autophagy induction, the mechanism by which mTOR regulates autophagy has remained elusive. Here, we identify that mTOR phosphorylates a mammalian homologue of Atg13 and the mammalian Atg1 homologues ULK1 and ULK2. The mammalian Atg13 binds both ULK1 and ULK2 and mediates the interaction of the ULK proteins with FIP200. The binding of Atg13 stabilizes and activates ULK and facilitates the phosphorylation of FIP200 by ULK, whereas knockdown of Atg13 inhibits autophagosome formation. Inhibition of mTOR by rapamycin or leucine deprivation, the conditions that induce autophagy, leads to dephosphorylation of ULK1, ULK2, and Atg13 and activates ULK to phosphorylate FIP200. These findings demonstrate that the ULK-Atg13-FIP200 complexes are direct targets of mTOR and important regulators of autophagy in response to mTOR signaling.