Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1.
Disruption of the Rag-Ragulator Complex by c17orf59 Inhibits mTORC1.
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DOI：
10.1016/j.celrep.2015.07.052
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发表时间：
2015-09-01
期刊：
影响因子：
8.8
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Schweitzer LD;Comb WC;Bar-Peled L;Sabatini DM
mTORC1控制调节细胞生长的关键过程，包括mRNA翻译、核糖体生物发生和自噬。环境氨基酸通过促进mTORC1募集到溶酶体的细胞质表面来激活mTORC1，其激酶在生长因子信号传导的下游被激活。mTORC1通过Rag gtpase进入溶酶体，Rag gtpase通过调节物（一种溶酶体结合的支架）连接到溶酶体膜上。在这里，我们发现c17orf59是一种调节因子相互作用蛋白，通过与溶酶体上的调节因子相互作用来调节mTORC1的活性。c17orf59与调节因子的结合阻止了调节因子与Rag GTPase在细胞和体外的相互作用，并降低Rag GTPase溶酶体的定位。c17orf59破坏rag -调节剂相互作用，通过阻止mTOR到达溶酶体，从而损害氨基酸对mTORC1的激活。通过破坏rag - regulator相互作用来抑制mTORC1， c17orf59的表达可能代表了mTORC1调节营养感知的另一种机制。氨基酸通过Rag gtpase诱导mTORC1募集到溶酶体表面，Rag gtpase被调节物拴在溶酶体膜上。c17orf59与调节因子相互作用，过表达破坏Rag-调节因子复合物，阻止Rag溶酶体定位，导致氨基酸存在时无法招募mTORC1。
mTORC1 controls key processes that regulate cell growth, including mRNA translation, ribosome biogenesis and autophagy. Environmental amino acids activate mTORC1 by promoting its recruitment to the cytosolic surface of the lysosome, where its kinase is activated downstream of growth factor signaling. mTORC1 is brought to the lysosome by the Rag GTPases, which are tethered to the lysosomal membrane by Ragulator, a lysosome-bound scaffold. Here, we identify c17orf59 as a Ragulator-interacting protein that regulates mTORC1 activity through its interaction with Ragulator at the lysosome. The binding of c17orf59 to Ragulator prevents Ragulator interaction with the Rag GTPases, both in cells and in vitro, and decreases Rag GTPase lysosomal localization. Disruption of the Rag-Ragulator interaction by c17orf59 impairs mTORC1 activation by amino acids by preventing mTOR from reaching the lysosome. By disrupting the Rag-Ragulator interaction to inhibit mTORC1, c17orf59 expression may represent another mechanism to modulate nutrient sensing by mTORC1. Amino acids induce recruitment of mTORC1 to the lysosomal surface through the Rag GTPases, which are tethered to the lysosomal membrane by Ragulator. c17orf59 interacts with Ragulator, and overexpression disrupts the Rag-Ragulator complex, preventing Rag lysosomal localization and leading to a failure to recruit mTORC1 in the presence of amino acids.