An Atg1/Atg13 Complex with Multiple Roles in TOR-mediated Autophagy Regulation
An Atg1/Atg13 Complex with Multiple Roles in TOR-mediated Autophagy Regulation
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DOI：
10.1091/mbc.e08-12-1250
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发表时间：
2009-04-01
影响因子：
3.3
通讯作者：
Neufeld, Thomas P.
中科院分区：
文献类型：
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作者：
Chang, Yu-Yun;Neufeld, Thomas P.
TOR激酶是响应营养条件的保守的自噬负调控因子，但信号转导描述了一种含有蛋白激酶Atg 1和磷蛋白Atg 13的复合物，该复合物在果蝇中作为这种调控的关键组分发挥作用。我们发现，敲除Atg 1或Atg 13导致类似的，选择性的自噬缺陷，以响应TOR失活。Atg 1在体内与TOR和Atg 13发生物理相互作用，Atg 1和Atg 13均以营养、TOR和Atg 1激酶依赖性方式磷酸化。与酵母相反，Atg 13的磷酸化在自噬条件下最大，并且不排除Atg 1-Atg 13缔合。Atg 13刺激Atg 1的自噬活性及其对细胞生长和TOR信号传导的抑制，部分是通过破坏TOR的正常运输。与正常Atg 13水平的作用相反，Atg 13表达增加抑制自噬体扩增和Atg 8/LC 3的募集，可能是通过降低Atg 1的稳定性并促进其抑制性TOR磷酸化。因此，Atg 1-Atg 13复合物在多个水平上起作用，以介导和调节营养依赖性自噬信号传导。
The TOR kinases are conserved negative regulators of autophagy in response to nutrient conditions, but the signaling describe a complex containing the protein kinase Atg1 and the phosphoprotein Atg13 that functions as a critical component of this regulation in Drosophila. We show that knockout of Atg1 or Atg13 results in a similar, selective defect in autophagy in response to TOR inactivation. Atg1 physically interacts with TOR and Atg13 in vivo, and both Atg1 and Atg13 are phosphorylated in a nutrient-, TOR- and Atg1 kinase-dependent manner. In contrast to yeast, phosphorylation of Atg13 is greatest under autophagic conditions and does not preclude Atg1-Atg13 association. Atg13 stimulates both the autophagic activity of Atg1 and its inhibition of cell growth and TOR signaling, in part by disrupting the normal trafficking of TOR. In contrast to the effects of normal Atg13 levels, increased expression of Atg13 inhibits autophagosome expansion and recruitment of Atg8/LC3, potentially by decreasing the stability of Atg1 and facilitating its inhibitory phosphorylation by TOR. Atg1-Atg13 complexes thus function at multiple levels to mediate and adjust nutrient- dependent autophagic signaling.