Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1

Guoxiang Jin, Szu Wei Lee, Xian Zhang, Zhen Cai, Yuan Gao, Ping Chieh Chou, Abdol Hossein Rezaeian, Fei Han, Chi Yun Wang, Juo Chin Yao, Zhaohui Gong, Chia Hsin Chan, Chih Yang Huang, Fuu Jen Tsai, Chang Hai Tsai, Shih Hsin Tu, Chih Hsiung Wu, Dos D. Sarbassov, Yuan Soon Ho, Hui Kuan Lin

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45 Citations (Scopus)

Abstract

The regulation of RagAGTP is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagAGTP, 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 RagAGTP 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.

Original languageEnglish
Pages (from-to)989-1000
Number of pages12
JournalMolecular Cell
Volume58
Issue number6
DOIs
Publication statusPublished - Jun 18 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Jin, G., Lee, S. W., Zhang, X., Cai, Z., Gao, Y., Chou, P. C., Rezaeian, A. H., Han, F., Wang, C. Y., Yao, J. C., Gong, Z., Chan, C. H., Huang, C. Y., Tsai, F. J., Tsai, C. H., Tu, S. H., Wu, C. H., Sarbassov, D. D., Ho, Y. S., & Lin, H. K. (2015). Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino-Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1. Molecular Cell, 58(6), 989-1000. https://doi.org/10.1016/j.molcel.2015.05.010