Jung, Jae Woo Macalino, Stephani Joy Y. Cui, Minghua Kim, Ji Eon Kim, Hye-Jin Song, Dae-Geun Nam, Seo Hee Kim, Semi Choi, Sun Lee, Jung Weon 2024-01-19T20:00:45Z 2024-01-19T20:00:45Z 2021-09-02 2019-06-04 1550-4131 https://pubs.kist.re.kr/handle/201004/119892 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. English CELL PRESS EPITHELIAL-MESENCHYMAL TRANSITION TM4SF5 PROTEIN IDENTIFICATION EXPRESSION INHIBITION ALIGNMENT SLC38A9 SENSORS CANCER Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling Article 10.1016/j.cmet.2019.03.005 1 CELL METABOLISM, v.29, no.6, pp.1306 - + CELL METABOLISM 29 6 1306 + scie scopus 000470097200009 2-s2.0-85066274326 Cell Biology Endocrinology & Metabolism Cell Biology Endocrinology & Metabolism Article EPITHELIAL-MESENCHYMAL TRANSITION TM4SF5 PROTEIN IDENTIFICATION EXPRESSION INHIBITION ALIGNMENT SLC38A9 SENSORS CANCER amino acid transporter arginine sensor homology modeling lysosome metabolism molecular docking modeling mTOR protein interaction tetraspanin trafficking TM4SF5