跨膜4L6家族成员5（TM4SF5）受精氨酸对mTORC1信号转导的影响，这一成果由首尔国立大学Jung Weon Lee团队取得。 该项研究成果发表在2019年4月4日出版的《Cell Metabolism》上。

研究人员发现，在精氨酸充足的情况下，跨膜4L6家族成员5 (TM4SF5)作为精氨酸感受器从质膜转移到溶酶体，并最终激活mTORC1/S6K1。TM4SF5结合精氨酸充分性激活的mTOR和组成结合的氨基酸转运体SLC38A9。当精氨酸充足时，TM4SF5与胞质精氨酸传感器Castor1结合减少，这使得TM4SF5介导的代谢氨基酸检测成为可能。TM4SF5可能通过其细胞外环直接结合游离的L-精氨酸进行外溢，突变体研究和同源性和分子对接模型证实了这一结果。因此，课题组人员提出溶酶体TM4SF5能够感知并使精氨酸外溢激活mTORC1/S6K1，而精氨酸-促生长因子在肝细胞癌中的作用，可能是通过阻断精氨酸感应器的抗TM4SF5试剂来实现的。

据介绍，靶向雷帕霉素复合物(mTORC1)的机制是溶酶体表面的一个信号枢纽，对溶酶体氨基酸起反应。虽然精氨酸在代谢上很重要，但精氨酸激活mTOR的生理传感器仍不清楚。

附：英文原文

Title: Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling

Author: Jae Woo Jung, Stephani Joy Y. Macalino, Minghua Cui, Semi Kim, Sun Choi, Jung Weon Lee

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

Abstract: The mechanistic target of rapamycin complex (mTORC1) is a signaling hub on the lysosome surface, responding to lysosomal amino acids. Although arginine is metabolically important, the physiological arginine sensor that activates mTOR remains unclear. Here, we show that transmembrane 4 L six family member 5 (TM4SF5) translocates from plasma membrane to lysosome upon arginine sufficiency and senses arginine, culminating in mTORC1/S6K1 activation. TM4SF5 bound active mTOR upon arginine sufficiency and constitutively bound amino acid transporter SLC38A9. TM4SF5 binding to the cytosolic arginine sensor Castor1 decreased upon arginine sufficiency, thus allowing TM4SF5-mediated sensing of metabolic amino acids. TM4SF5 directly bound free L-arginine via its extracellular loop possibly for the efflux, being supported by mutant study and homology and molecular docking modeling. Therefore, we propose that lysosomal TM4SF5 senses and enables arginine efflux for mTORC1/S6K1 activation, and arginine-auxotroph in hepatocellular carcinoma may be targeted by blocking the arginine sensing using anti-TM4SF5 reagents.

DOI: https://doi.org/10.1016/j.cmet.2019.03.005

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30133-0