The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway.
The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway.
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DOI：
10.1016/j.cell.2016.02.035
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发表时间：
2016-03-24
期刊：
影响因子：
64.5
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Chantranupong L;Scaria SM;Saxton RA;Gygi MP;Shen K;Wyant GA;Wang T;Harper JW;Gygi SP;Sabatini DM
氨基酸通过RAG GTP酶向mTOR复合体I(MTORC1)生长途径传递信号。多种不同的复合体调节RAGS，包括GTP酶激活蛋白GATOR1和未知分子功能的正调节因子GATOR2。精氨酸刺激细胞可以激活mTORC1，但它是如何被感知的还不是很清楚。最近，SLC38A9被鉴定为一种可能的溶酶体精氨酸感受器，精氨酸激活mTORC1需要精氨酸，但精氨酸剥夺如何抑制mTORC1尚不清楚。在这里，我们证明了CASTOR1，一个以前没有特征的蛋白质，与GATOR2相互作用，并且是精氨酸剥夺所必需的，以抑制mTORC1。CASTOR1与相关蛋白CASTOR2同源二聚，也可异源二聚。精氨酸通过与CASTOR1结合来破坏CASTOR1-GATOR2复合体，其解离常数为~30μM，其与精氨酸的结合能力是精氨酸激活细胞内mTORC1所必需的。总而言之，这些结果确立了CASTOR1作为mTORC1途径的精氨酸传感器。
Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway.