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

Jae Woo Jung, Stephani Joy Y. Macalino, Minghua Cui, Ji Eon Kim, Hye Jin Kim, Dae Geun Song, Seo Hee Nam, Semi Kim, Sun Choi, Jung Weon Lee

Research output: Contribution to journalArticlepeer-review

46 Scopus citations

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. Lysosomal arginine is involved in mTORC1/S6K1 activation for cell growth. Jung et al. identify TM4SF5 as a membrane-based sensor of physiologic levels of arginine. TM4SF5 forms a complex with mTOR and the amino acid transporter SLC38A9 on lysosomal membranes in an arginine-regulated manner, leading to arginine efflux and mTOR/S6K1 activation.

Original languageEnglish
Pages (from-to)1306-1319.e7
JournalCell Metabolism
Volume29
Issue number6
DOIs
StatePublished - 4 Jun 2019

Bibliographical note

Funding Information:
This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning ( NRF-2018M3A9C8020027 to S.K. and 2017R1A2B3005015 to J.W.L.), for the Tumor Microenvironment GCRC ( 2011-0030001 ) and for Medicinal Bioconvergence Research Center ( NRF-2013M3A6A4044019 ) to J.W.L, and Fibrosis Control Center (MRC) (No. 2018R1A5A2025286 ) and Mid-career Researcher Program ( NRF-2017R1A2B4010084 ) funded by the Ministry of Science and ICT (MSIT) through the National Research Foundation of Korea (NRF) to S.C. We also thank the Korea Institute of Science and Technology Information (KISTI) Supercomputing Center for providing computing resources.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

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

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