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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
Molecular cell, 06/2015, Letnik: 58, Številka: 6Journal Article
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. Display omitted •Skp2 mediates amino-acid-induced RagA ubiquitination and GATOR1 recruitment•Skp2 is a negative feedback regulator of amino-acid-dependent mTORC1 signaling•Skp2 promotes autophagy but inhibits cell size and cilia growth by mTORC1 repression Jin et al. identify a critical molecular mechanism by which amino acids initiate a negative feedback loop for amino-acid-dependent mTORC1signaling. The findings demonstrate that mTORC1 signaling is properly restricted in the physiological condition under continuous amino acid stimulation, thus preventing mTORC1 hyperactivation and cellular functional disorders.
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