德国科隆大学Constantinos Demetriades团队近期取得重要工作进展，他们研究发现Rag GTPase二聚体代码定义了氨基酸对mTORC1的调节作用。相关论文2022年9月12日在线发表于《自然-细胞生物学》杂志上。

研究人员使用表达单个Rag异二聚体的转基因细胞系，他们发现了一个Rag二聚体代码，它决定了氨基酸如何调节mTORC1。首先，RagC/D差异定义了mTORC1下游底物的特异性，其中RagD促进其溶酶体底物TFEB/TFE3的磷酸化，而两种Rags都参与非溶酶体底物（如S6K）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mTORC1募集到溶酶体。

此外，RagA/B指定了对氨基酸去除的信号应答反应，表达RagB的细胞即使在饥饿时也能保持溶酶体和活性mTORC1。总体而言，他们的研究结果揭示了Rag旁系同源物在调节mTORC1方面的关键差异，并强调了Rag基因复制和多样化是哺乳动物进化中的潜在影响事件。

据了解，氨基酸可用性通过异二聚体Rag GTPase复合体控制mTORC1的活性，该复合体在溶酶体表面起支架作用，将mTORC1及其激活剂和效应剂聚集在一起。哺乳动物细胞表达它们的Rag蛋白(RagA-D)，形成由RagA/B结合RagC/D组成的二聚体。传统上，Rag同源对(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。

附：英文原文

Title: A Rag GTPase dimer code defines the regulation of mTORC1 by amino acids

Author: Gollwitzer, Peter, Grtzmacher, Nina, Wilhelm, Sabine, Kmmel, Daniel, Demetriades, Constantinos

Issue&Volume: 2022-09-12

Abstract: 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.

DOI: 10.1038/s41556-022-00976-y

Source: https://www.nature.com/articles/s41556-022-00976-y