A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids.
A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids.
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DOI：
10.1038/s41556-022-00976-y
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发表时间：
2022-09
影响因子：
21.3
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中科院分区：
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氨基酸利用率通过异二聚体Rag GT3复合物控制mTORC 1活性，该复合物在溶酶体表面起支架作用，将mTORC 1与其激活剂和效应物结合在一起。哺乳动物细胞表达四种Rag蛋白（RagA-D），其形成由结合到RagC/D的RagA/B组成的二聚体。传统上，RagA/B和RagC/D被认为是功能冗余的，在大多数研究中，四种二聚体组合可互换使用。在这里，通过使用表达单个Rag异二聚体的转基因细胞系，我们发现了一个决定氨基酸如何调节mTORC 1的Rag二聚体代码。首先，RagC/D差异性地定义了mTORC 1下游的底物特异性，其中RagD促进其溶酶体底物TFEB/TFE 3的磷酸化，而两个Rag都参与非溶酶体底物如S6 K的磷酸化。从机制上讲，RagD通过增加对锚定LAMTOR复合物的亲和力，更有效地将mTORC 1募集到溶酶体。此外，RagA/B指定了对氨基酸去除的信号传导反应，其中RagB表达细胞即使在饥饿时也保持溶酶体和活性mTORC 1。总的来说，我们的研究结果揭示了Rag旁系同源物在mTORC 1调控方面的关键质的差异，并强调了Rag基因的重复和多样化是哺乳动物进化中潜在的影响事件。Gollwitzer、Grützmacher et al.和Figlia et al.确定了各种Rag GT3基因和亚型差异性调节mTORC 1活性，并明显调节哺乳动物细胞对氨基酸可用性的反应性。
Amino acid availability controls mTORC1 activity via a heterodimeric Rag GTPase complex that functions as a scaffold at the lysosomal surface, bringing together mTORC1 with its activators and effectors. Mammalian cells express four Rag proteins (RagA–D) that form dimers composed of RagA/B bound to RagC/D. Traditionally, the Rag paralogue pairs (RagA/B and RagC/D) are referred to as functionally redundant, with the four dimer combinations used interchangeably in most studies. Here, by using genetically modified cell lines that express single Rag heterodimers, we uncover a Rag dimer code that determines how amino acids regulate mTORC1. First, RagC/D differentially define the substrate specificity downstream of mTORC1, with RagD promoting phosphorylation of its lysosomal substrates TFEB/TFE3, while both Rags are involved in the phosphorylation of non-lysosomal substrates such as S6K. Mechanistically, RagD recruits mTORC1 more potently to lysosomes through increased affinity to the anchoring LAMTOR complex. Furthermore, RagA/B specify the signalling response to amino acid removal, with RagB-expressing cells maintaining lysosomal and active mTORC1 even upon starvation. Overall, our findings reveal key qualitative differences between Rag paralogues in the regulation of mTORC1, and underscore Rag gene duplication and diversification as a potentially impactful event in mammalian evolution. Gollwitzer, Grützmacher et al. and Figlia et al. establish that the various Rag GTPase genes and isoforms differentially regulate mTORC1 activity and distinctly modulate the responsiveness of mammalian cells to amino acid availability.
影响因子：
21.3
作者：
通讯作者：
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