2. Academic Validation
  3. Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling

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

  • Cell Metab. 2019 Jun 4;29(6):1306-1319.e7. doi: 10.1016/j.cmet.2019.03.005.
Jae Woo Jung 1,  Stephani Joy Y Macalino 2,  Minghua Cui 2,  Ji Eon Kim 3,  Hye-Jin Kim 3,  Dae-Geun Song 4,  Seo Hee Nam 3,  Semi Kim 5,  Sun Choi 6,  Jung Weon Lee 7
Affiliations

Affiliations

  • 1 Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, South Korea.
  • 2 National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea.
  • 3 Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea.
  • 4 Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea; Systems Biotechnology Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do 25451, South Korea.
  • 5 Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejon 34141, Republic of Korea.
  • 6 National Leading Research Laboratory of Molecular Modeling & Drug Design, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, South Korea. Electronic address: sunchoi@ewha.ac.kr.
  • 7 Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, South Korea; Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea. Electronic address: jwl@snu.ac.kr.
PMID: 30956113 DOI: 10.1016/j.cmet.2019.03.005
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.

Keywords

TM4SF5; amino acid transporter; arginine sensor; homology modeling; lysosome; mTOR; metabolism; molecular docking modeling; protein interaction; tetraspanin trafficking.

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