德国马克斯·普朗克衰老生物学研究所Constantinos Demetriades研究组揭示了，响应不同氨基酸来源时mTORC1信号的空间和功能分离。这一研究成果于2024年10月9日在线发表在国际学术期刊《自然—细胞生物学》上。

研究人员通过多种药理学和遗传手段扰乱溶酶体的氨基酸（AA）感应和蛋白质回收机制，揭示了哺乳动物细胞中机械/哺乳动物雷帕霉素靶蛋白复合物1（mTORC1）调控和下游功能的空间分离。溶酶体和非溶酶体mTORC1在响应不同氨基酸来源时分别磷酸化不同的底物。

此外，研究人员发现部分mTOR定位于溶酶体是由于基础性的溶酶体蛋白水解局部提供新氨基酸，即使在细胞外营养充足的条件下也是如此，而细胞质中的mTORC1则由外源性氨基酸调控。

总体而言，该研究大大拓展了AA对mTORC1调控的拓扑学理解，提示存在独特的、Rag和溶酶体非依赖性机制，在其他亚细胞位置调控其活性。鉴于mTORC1信号和AA感应在人体衰老和疾病中的重要性，该发现可能为识别功能特异性mTORC1调控因子铺平道路，从而为发现更有效的药物靶点提供新的方向，以应对未来mTORC1活性失调相关的疾病。

据介绍，AA可用性是通过调控mTORC1活性来决定细胞生长的关键因素。根据该领域的主流模型，氨基酸充足性通过异二聚体Rag GTP酶在溶酶体表面驱动mTORC1的募集和激活，从而协调大多数细胞过程。然而，关于溶酶体对mTORC1的调控机制及其对效应蛋白的作用位置仍不清楚。

附：英文原文

Title: Spatial and functional separation of mTORC1 signalling in response to different amino acid sources

Author: Fernandes, Stephanie A., Angelidaki, Danai-Dimitra, Nchel, Julian, Pan, Jiyoung, Gollwitzer, Peter, Elkis, Yoav, Artoni, Filippo, Wilhelm, Sabine, Kovacevic-Sarmiento, Marija, Demetriades, Constantinos

Issue&Volume: 2024-10-09

Abstract: Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic. Here, by using multiple pharmacological and genetic means to perturb the lysosomal AA-sensing and protein recycling machineries, we describe the spatial separation of mTORC1 regulation and downstream functions in mammalian cells, with lysosomal and non-lysosomal mTORC1 phosphorylating distinct substrates in response to different AA sources. Moreover, we reveal that a fraction of mTOR localizes at lysosomes owing to basal lysosomal proteolysis that locally supplies new AAs, even in cells grown in the presence of extracellular nutrients, whereas cytoplasmic mTORC1 is regulated by exogenous AAs. Overall, our study substantially expands our knowledge about the topology of mTORC1 regulation by AAs and hints at the existence of distinct, Rag- and lysosome-independent mechanisms that control its activity at other subcellular locations. Given the importance of mTORC1 signalling and AA sensing for human ageing and disease, our findings will probably pave the way towards the identification of function-specific mTORC1 regulators and thus highlight more effective targets for drug discovery against conditions with dysregulated mTORC1 activity in the future.

DOI: 10.1038/s41556-024-01523-7

Source: https://www.nature.com/articles/s41556-024-01523-7