德国海德堡大学Aurelio A. Teleman团队近期取得重要工作进展，他们研究发现脑部富集的RagB亚型通过GATOR1的抑制作用调节mTORC1的动态活性。这一研究成果2022年9月12日在线发表于《自然—细胞生物学》杂志上。

尽管假设RagA和B旁系同源物在功能上是等效的，但研究人员发现，在神经元中高度表达的RagB亚型通过抑制RagA/B GTP酶激活蛋白GATOR1，使mTORC1对营养缺乏具有抵抗力。研究人员进一步表明，在一些肿瘤中观察到RagB同种型的高表达，揭示了一种替代策略，癌细胞可以通过这种策略在低营养情况下保留升高的mTORC1。

据介绍，雷帕霉素复合物1（mTORC1）的机械靶点可感知营养物质的可用性以适当调节细胞合成代谢和分解代谢。在营养限制期间，动物的不同器官的反应是不一样的，重要的器官相对来说会受到伤害。这提出了mTORC1在不同细胞类型中受到差异调节的可能性，但对此机制知之甚少。Rag GTPases，RagA或RagB与RagC或RagD结合，以营养依赖的方式将mTORC1拴在溶酶体上，mTORC1被激活。

附：英文原文

Title: Brain-enriched RagB isoforms regulate the dynamics of mTORC1 activity through GATOR1 inhibition

Author: Figlia, Gianluca, Mller, Sandra, Hagenston, Anna M., Kleber, Susanne, Roiuk, Mykola, Quast, Jan-Philipp, ten Bosch, Nora, Carvajal Ibaez, Damian, Mauceri, Daniela, Martin-Villalba, Ana, Teleman, Aurelio A.

Issue&Volume: 2022-09-12

Abstract: Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to appropriately regulate cellular anabolism and catabolism. During nutrient restriction, different organs in an animal do not respond equally, with vital organs being relatively spared. This raises the possibility that mTORC1 is differentially regulated in different cell types, yet little is known about this mechanistically. The Rag GTPases, RagA or RagB bound to RagC or RagD, tether mTORC1 in a nutrient-dependent manner to lysosomes where mTORC1 becomes activated. Although the RagA and B paralogues were assumed to be functionally equivalent, we find here that the RagB isoforms, which are highly expressed in neurons, impart mTORC1 with resistance to nutrient starvation by inhibiting the RagA/B GTPase-activating protein GATOR1. We further show that high expression of RagB isoforms is observed in some tumours, revealing an alternative strategy by which cancer cells can retain elevated mTORC1 upon low nutrient availability.

DOI: 10.1038/s41556-022-00977-x

Source: https://www.nature.com/articles/s41556-022-00977-x