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GATOR-Rag GTPase通路抑制了由溶酶衍生氨基酸的mTORC1激活

Geoffrey G Hesketh¹, Fotini Papazotos¹, Judy Pawling¹

¹Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.

Science (New York, N.Y.)

|October 16, 2020

概括

营养感应蛋白复合体mTORC1由不同的氨基酸来源激活. 瘤性Ras驱动的巨细胞激活mTORC1独立于GATOR-Rag通路,揭示了细胞生长调节的新见解.

科学领域:

细胞生物学
分子生物学
生物化学

背景情况:

拉巴胺复合物1 (mTORC1) 的机理性标是细胞生长的关键调节剂,将营养的可用性与合成过程相结合.
mTORC1的激活通常是通过GATOR-Rag GTPase途径对足够的细胞外氨基酸的反应.
从 lysosomal 蛋白质降解到 mTORC1 的氨基酸信号仍然不完全理解.

研究的目的:

阐明由蛋白质降解产生的氨基酸激活mTORC1的机制.
调查瘤性Ras驱动的巨细胞在提供mTORC1激活的氨基酸中的作用.
要确定这种激活途径是否依赖于正规的GATOR-Rag GTPase信号.

主要方法:

使用瘤性Ras表达的细胞培养模型来诱导巨细胞.
使用生物化学测试来测量mTORC1活动.
使用遗传学和药理学方法研究了HOPS复合物和GATOR-Rag途径组件的参与.

主要成果:

确定了一种新途径,其中由瘤性Ras驱动的氨基酸激活mTORC1.
证明这种激活是独立于GATOR-Rag GTPase路径的.
显示HOPS复合体对于这种mTORC1刺激至关重要.
通过GATOR-Rag GTPase路径对该路径进行负调节.

结论:

不同的氨基酸来源通过单独的,但协调的信号通路激活mTORC1.
瘤性巨细胞形成一个独立于Rag GTPase的mTORC1激活路径.
这些发现突显了mTORC1在晚期内细胞器官中的复杂调节,以应对营养的可用性.

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