WAC 通过作为 TTT 与 Pontin/Reptin 复合物的衔接子来调节 mTOR 活性。
WAC Regulates mTOR Activity by Acting as an Adaptor for the TTT and Pontin/Reptin Complexes.
作者信息
David-Morrison Gabriela, Xu Zhen, Rui Yan-Ning, Charng Wu-Lin, Jaiswal Manish, Yamamoto Shinya, Xiong Bo, Zhang Ke, Sandoval Hector, Duraine Lita, Zuo Zhongyuan, Zhang Sheng, Bellen Hugo J
机构信息
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
The Brown Foundation Institute of Molecular Medicine, The University of Texas Medical School at Houston, Houston, TX 77030, USA.
出版信息
Dev Cell. 2016 Jan 25;36(2):139-51. doi: 10.1016/j.devcel.2015.12.019.
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. Under 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.
通过雷帕霉素机制性靶标复合物1（mTORC1）感知能量状态的能力在代谢调节中至关重要。TTT-Pontin/Reptin复合物的组装对能量状态的变化有反应。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mTORC1激活至关重要。我们发现WAC是能量介导的mTORC1活性的调节因子。在旨在分离导致神经元功能障碍的突变的果蝇筛选中，我们鉴定出了WAC的同源物wacky。wacky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）具有保守的物理相互作用，Pontin和Reptin与TTT复合物结合以调节mTORC1的能量依赖性激活。WAC以能量依赖的方式促进TTT与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。
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