Schweitzer Lawrence D, Comb William C, Bar-Peled Liron, Sabatini David M
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, MIT, Cambridge, MA 02139, USA; Broad Institute, Cambridge, MA 02142, USA; The David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
Cell Rep. 2015 Sep 1;12(9):1445-55. doi: 10.1016/j.celrep.2015.07.052. Epub 2015 Aug 20.
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.
mTORC1控制着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。环境中的氨基酸通过促进mTORC1募集到溶酶体的胞质表面来激活它，在那里其激酶在生长因子信号下游被激活。Rag GTP酶将mTORC1带到溶酶体，Rag GTP酶通过Ragulator（一种与溶酶体结合的支架）拴系在溶酶体膜上。在这里，我们鉴定出c17orf59是一种与Ragulator相互作用的蛋白质，它通过在溶酶体处与Ragulator相互作用来调节mTORC1活性。在细胞和体外，c17orf59与Ragulator的结合都会阻止Ragulator与Rag GTP酶相互作用，并降低Rag GTP酶在溶酶体的定位。c17orf59对Rag-Ragulator相互作用的破坏通过阻止mTOR到达溶酶体而损害氨基酸对mTORC1的激活。通过破坏Rag-Ragulator相互作用来抑制mTORC1，c17orf59的表达可能代表了另一种调节mTORC1对营养感知的机制。
