Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity.
Amino Acids Enhance Polyubiquitination of Rheb and Its Binding to mTORC1 by Blocking Lysosomal ATXN3 Deubiquitinase Activity.
复制标题
氨基酸通过阻断溶酶体ATXN3去泛素化酶活性增强Rheb的多聚泛素化及其与mTORC 1的结合。
DOI：
10.1016/j.molcel.2020.10.004
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发表时间：
2020-11-05
期刊：
影响因子：
16
通讯作者：
Inoki K
中科院分区：
文献类型：
--
作者：
Yao Y;Hong S;Ikeda T;Mori H;MacDougald OA;Nada S;Okada M;Inoki K
氨基酸诱导的溶酶体mTORC1通过Rag GTPase定位是其被Rheb GTPase激活的关键步骤。然而，mTORC1如何与溶酶体上的Rheb相互作用仍然难以捉摸。我们报道氨基酸增强Rheb （Ub-Rheb）的多泛素化，这显示出对mTORC1的强烈结合偏好并支持其激活，而Ub-Rheb则受到随后的降解。在机制上，我们确定ATXN3是一种Ub-Rheb去泛素酶，其溶酶体定位被活性rag阻断，以响应氨基酸刺激。一致地，在溶酶体上缺乏功能性rag的细胞积累了Ub-Rheb，并且阻断其降解激发了溶酶体mTORC1的强大定位及其在没有调节- rag系统的情况下的激活。因此，Rheb的多泛素化是一种重要的翻译后修饰，它促进了mTORC1在溶酶体上与Rheb的结合，是氨基酸与生长因子信号传导之间的另一种串扰，从而激活mTORC1。Yao等人证明氨基酸增强了溶酶体Rheb （Ub-Rheb）的多泛素化，后者对mTORC1具有很强的结合偏好，并支持氨基酸诱导的mTORC1激活。从机制上讲，我们发现Ub-Rheb被ATXN3去泛素化，其中溶酶体定位被无活性的Rag gtpase增强。
Amino acid-induced lysosomal mTORC1 localization through the Rag GTPases is a critical step for its activation by Rheb GTPase. However, how the mTORC1 interacts with Rheb on the lysosome remains elusive. We report that amino acids enhance the polyubiquitination of Rheb (Ub-Rheb), which shows a strong binding preference for mTORC1 and supports its activation, while the Ub-Rheb is subjected to subsequent degradation. Mechanistically, we identified ATXN3 as a Ub-Rheb deubiquitinase whose lysosomal localization is blocked by the active Rags in response to amino acid stimulation. Consistently, cells lacking functional Rags on the lysosome accumulate Ub-Rheb, and blockade of its degradation instigates robust lysosomal mTORC1 localization and its activation without the Ragulator-Rag system. Thus, polyubiquitination of Rheb is an important post-translational modification, which facilitates the binding of mTORC1 to Rheb on the lysosome and is another crosstalk between the amino acid and growth factor signaling for mTORC1 activation. Yao et al. demonstrate that amino acids enhance the polyubiquitination of lysosomal Rheb (Ub-Rheb) which has a strong binding preference for mTORC1 and supports amino acid-induced mTORC1 activation. Mechanistically, we identified that the Ub-Rheb is deubiquitinated by ATXN3, of which lysosomal localization is enhanced by the inactive Rag GTPases.
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