The association of AMPK with ULK1 regulates autophagy.
The association of AMPK with ULK1 regulates autophagy.
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DOI：
10.1371/journal.pone.0015394
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发表时间：
2010-11-03
期刊：
影响因子：
3.7
通讯作者：
Wang HG
中科院分区：
文献类型：
--
作者：
Lee JW;Park S;Takahashi Y;Wang HG
自噬是一种高度协调的细胞内体降解过程，可被各种环境胁迫激活。丝氨酸/苏氨酸激酶ULK1，与其酵母同源物Atg1一样，是自噬的关键启动物，受mTOR激酶负调控。然而，控制mTOR对ulk1介导的自噬抑制作用的分子机制尚不完全清楚。在这里，我们确定了AMPK，一个中心能量传感器，作为一个新的ulk1结合伙伴。我们发现AMPK与ULK1的PS结构域结合，这种相互作用是ULK1介导的自噬所必需的。有趣的是，AICAR激活AMPK诱导14-3-3结合AMPK- ulk1 - mtorc1复合物，这与猛禽Ser792磷酸化和mTOR失活相吻合。一致地，AICAR在表达野生型猛禽的tsc2缺陷细胞中诱导自噬，而不表达缺乏AMPK磷酸化位点（Ser722和Ser792）的突变型猛禽。综上所述，这些结果表明AMPK与ULK1的关联在诱导自噬中起着重要作用，至少在一定程度上是通过磷酸化raptor来解除mTOR对ULK1自噬复合物的抑制作用。
Autophagy is a highly orchestrated intracellular bulk degradation process that is activated by various environmental stresses. The serine/threonine kinase ULK1, like its yeast homologue Atg1, is a key initiator of autophagy that is negatively regulated by the mTOR kinase. However, the molecular mechanism that controls the inhibitory effect of mTOR on ULK1-mediated autophagy is not fully understood. Here we identified AMPK, a central energy sensor, as a new ULK1-binding partner. We found that AMPK binds to the PS domain of ULK1 and this interaction is required for ULK1-mediated autophagy. Interestingly, activation of AMPK by AICAR induces 14-3-3 binding to the AMPK-ULK1-mTORC1 complex, which coincides with raptor Ser792 phosphorylation and mTOR inactivation. Consistently, AICAR induces autophagy in TSC2-deficient cells expressing wild-type raptor but not the mutant raptor that lacks the AMPK phosphorylation sites (Ser722 and Ser792). Taken together, these results suggest that AMPK association with ULK1 plays an important role in autophagy induction, at least in part, by phosphorylation of raptor to lift the inhibitory effect of mTOR on the ULK1 autophagic complex.
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