Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling
- 주제(기타) Cell Biology; Endocrinology & Metabolism
- 설명문(일반) [Jung, Jae Woo; Lee, Jung Weon] Seoul Natl Univ, Interdisciplinary Program Genet Engn, Seoul 08826, South Korea; [Macalino, Stephani Joy Y.; Cui, Minghua] Ewha Womans Univ, Coll Pharm, Natl Leading Res Lab Mol Modeling & Drug Design, Seoul 03760, South Korea; [Macalino, Stephani Joy Y.; Cui, Minghua] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Kim, Ji Eon; Kim, Hye-Jin; Song, Dae-Geun; Nam, Seo Hee; Choi, Sun; Lee, Jung Weon] Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Dept Pharm, Seoul 08826, South Korea; [Song, Dae-Geun] KIST, Syst Biotechnol Res Ctr, Gangneung Si 25451, Gangwon Do, South Korea; [Kim, Semi] Immunotherapy Convergence Res Ctr, Korea Res Inst Biosci & Biotechnol, Daejon 34141, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Bronze
- 발행기관 CELL PRESS
- 발행년도 2019
- URI http://www.dcollection.net/handler/ewha/000000160044
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.cmet.2019.03.005
- PubMed https://pubmed.ncbi.nlm.nih.gov/30956113
초록/요약
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.
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