The Ubiquitination of RagA GTPase by RNF152 Negatively Regulates mTORC1 Activation
The Ubiquitination of RagA GTPase by RNF152 Negatively Regulates mTORC1 Activation
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RNF152 泛素化 RagA GTPase 负向调节 mTORC1 激活
DOI：
10.1016/j.molcel.2015.03.033
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发表时间：
2015-06-04
期刊：
影响因子：
16
通讯作者：
Wang, Ping
中科院分区：
文献类型：
--
作者：
Deng, Lu;Jiang, Cong;Wang, Ping
MTORC1是调节细胞生长和代谢以响应各种环境刺激所必需的。异二聚体RAG GTP酶是氨基酸介导的溶酶体mTORC1激活所必需的。然而，氨基酸调节RAG激活的机制仍不完全清楚。在这里，我们通过靶向RAGA进行K63连接的泛素化，确定了溶酶体锚定的E3泛素连接酶RNF152是mTORC1途径的重要负调控因子。RNF152以氨基酸敏感的方式与RAGA相互作用并泛化RAGA。RAGA泛素化位点的突变取消了RNF152的这一作用，并增强了RAGA介导的mTORC1的激活。RNF152泛素化在RAGA上产生一个锚点来招募其抑制剂GATOR1，GATOR1是Rag GTP酶的间隙复合体。RNF152基因敲除导致mTORC1的过度激活，并保护细胞免受氨基酸饥饿诱导的自噬。因此，本研究揭示了RNF152介导的RNF152介导的K63连接的RAGA多泛素化对mTORC1信号的调节机制。
mTORC1 is essential for regulating cell growth and metabolism in response to various environmental stimuli. Heterodimeric Rag GTPases are required for amino-acid-mediated mTORC1 activation at the lysosome. However, the mechanism by which amino acids regulate Rag activation remains not fully understood. Here, we identified the lysosome-anchored E3 ubiquitin ligase RNF152 as an essential negative regulator of the mTORC1 pathway by targeting RagA for K63-linked ubiquitination. RNF152 interacts with and ubiquitinates RagA in an amino-acid-sensitive manner. The mutation of RagA ubiquitination sites abolishes this effect of RNF152 and enhances the RagA-mediated activation of mTORC1. Ubiquitination by RNF152 generates an anchor on RagA to recruit its inhibitor GATOR1, a GAP complex for Rag GTPases. RNF152 knockout results in the hyperactivation of mTORC1 and protects cells from amino-acid-starvation-induced autophagy. Thus, this study reveals a mechanism for regulation of mTORC1 signaling by RNF152-mediated K63-linked poly-ubiquitination of RagA.