WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes.
WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes.
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DOI：
10.1016/j.devcel.2015.12.019
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发表时间：
2016-01-25
影响因子：
11.8
通讯作者：
Bellen HJ
中科院分区：
文献类型：
--
作者：
David-Morrison G;Xu Z;Rui YN;Charng WL;Jaiswal M;Yamamoto S;Xiong B;Zhang K;Sandoval H;Duraine L;Zuo Z;Zhang S;Bellen HJ
感知能量状态的能力对于通过雷帕霉素复合物 1 (mTORC1) 的机制靶标调节新陈代谢至关重要。 TTT-Pontin/Reptin 复合物的组装对能量状态的变化做出反应。在能量充足的条件下，TTT-Pontin/Reptin 复合物促进 mTORC1 二聚化和 mTORC1-Rag 相互作用，这对于 mTORC1 激活至关重要。我们证明 WAC 是能量介导的 mTORC1 活性的调节剂。在旨在分离导致神经元功能障碍的突变的果蝇筛选中，我们发现了 WAC 的同源物 wacky。 Wacky 的缺失会导致神经退行性变、mTOR 活性缺陷和自噬增加。 Wacky 和 WAC 与 mTOR 及其调节因子（包括 Pontin 和 Reptin）保留了物理相互作用，它们与 TTT 复合物结合，调节 mTORC1 的能量依赖性激活。 WAC以能量依赖性方式促进TTT和Pontin/Reptin之间的相互作用，从而通过促进mTORC1二聚化和mTORC1-Rag相互作用来促进mTORC1活性。
The ability to sense energy status is crucial in the regulation of metabolism via the mechanistic Target of Rapamycin Complex 1 (mTORC1). The assembly of the TTT-Pontin/Reptin complex is responsive to changes in energy status. In energy sufficient conditions, the TTT-Pontin/Reptin complex promotes mTORC1 dimerization and mTORC1-Rag interaction, which are critical for mTORC1 activation. We show that WAC is a regulator of energy-mediated mTORC1 activity. In a Drosophila screen designed to isolate mutations that cause neuronal dysfunction, we identified wacky, the homolog of WAC. Loss of Wacky leads to neurodegeneration, defective mTOR activity and increased autophagy. Wacky and WAC have conserved physical interactions with mTOR and its regulators, including Pontin and Reptin which bind to the TTT complex to regulate energy-dependent activation of mTORC1. WAC promotes the interaction between TTT and Pontin/Reptin in an energy-dependent manner, thereby promoting mTORC1 activity by facilitating mTORC1 dimerization and mTORC1-Rag interaction.