拉格-Ragulator是mTORC1营养感应通路物理架构的中心组织者
Max L Valenstein1,2,3,4, Pranav V Lalgudi2,3, Xin Gu2,3,4
1Department of Medicine, Massachusetts General Hospital, Boston, MA 02114.
概括
拉格GTPases和Ragulator复合体对于拉帕素复合体1 (mTORC1) 途径的机械性标的营养感应至关重要. 这些组件组织mTORC1路径.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 生物化学 生物化学
背景情况:
- 拉巴胺素复合体1 (mTORC1) 途径的机械性标是细胞生长和新陈代谢的关键调节者,对营养素等环境线索做出反应.
- 氨基酸通过改变Rag GTPases的关氨酸核酸加载状态向mTORC1发出信号,这些状态将mTORC1招募到 lysosome中进行激活.
- 拉格GTPases和相关的调节复合体 (GATOR1,GATOR2,KICSTOR) 通过尚未完全阐明的机制定位到 lysosome.
研究的目的:
- 研究Rag GTPases和Ragulator复合体在mTORC1通路的溶酶体局部化和激活中的作用.
- 阐明营养信号被转化为 lysosome 上的 mTORC1 的机制.
- 为了确定 lysosomal 局部化对于 mTORC1 营养感应的必要性.
主要方法:
- 对细胞进行基因操纵,使其缺乏Rag GTPase/Ragulator通路的特定成分.
- 分析mTORC1活动和局部化,以响应氨基酸的可用性.
- 生物化学和细胞成像技术用于研究调节复合物的组装和贩运.
主要成果:
- 在缺乏Rag GTPases或Ragulator的细胞中,mTORC1对氨基酸不敏感.
- 拉格GTPases和Ragulator对于GATOR1,GATOR2和KICSTOR的溶酶体招募是不可或缺的,它们组成了一个"GATOR"超级复合体.
- RagA/B 的核酸状态和氨基酸载体 SLC38A9 影响了 GATOR 的 lysosomal 关联.
- 将Ragulator重新定位到线粒体并不能使营养调节的mTORC1招募到这个细胞器.
结论:
- 拉格-调节器复合体作为mTORC1营养感应通路的物理架构的中央组织者.
- 溶酶体表面信号转导是mTORC1激活的先决条件.
- 这项研究揭示了 lysosomal 局部化在营养介导的 mTORC1 调节中的关键作用.
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