Jin Guoxiang, Lee Szu-Wei, Zhang Xian, Cai Zhen, Gao Yuan, Chou Ping-Chieh, Rezaeian Abdol Hossein, Han Fei, Wang Chi-Yun, Yao Juo-Chin, Gong Zhaohui, Chan Chia-Hsin, Huang Chih-Yang, Tsai Fuu-Jen, Tsai Chang-Hai, Tu Shih-Hsin, Wu Chih-Hsiung, Sarbassov Dos D, Ho Yuan-Soon, Lin Hui-Kuan
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA.
Mol Cell. 2015 Jun 18;58(6):989-1000. doi: 10.1016/j.molcel.2015.05.010. Epub 2015 Jun 4.
The regulation of RagA(GTP) is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagA(GTP), how GATOR1 is recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagA(GTP) hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions.
RagA（GTP）的调节对于氨基酸诱导的mTORC1激活至关重要。尽管GATOR1复合物已被确定为通过水解RagA（GTP）来对mTORC1起负调节作用，但GATOR1如何被招募到RagA以减弱mTORC1信号传导仍不清楚。此外，在氨基酸刺激后mTORC1信号传导如何终止也尚不清楚。我们发现，GATOR1被招募到RagA是由氨基酸以mTORC1依赖性方式诱导的。Skp2 E3连接酶驱动RagA的K63连接的泛素化，这促进了GATOR1的招募和RagA（GTP）的水解，从而提供一个负反馈环以减弱mTORC1向溶酶体的招募并防止mTORC1过度激活。我们进一步证明，Skp2通过RagA泛素化和mTORC1抑制促进自噬，但抑制细胞大小和纤毛生长。因此，我们提出一种负反馈机制，即Skp2介导的RagA泛素化在持续的氨基酸刺激下招募GATOR1以限制mTORC1信号传导，这是维持适当细胞功能的关键机制。
