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

Title
Transmembrane 4 L Six Family Member 5 Senses Arginine for mTORC1 Signaling
Authors
송대근Jae Woo JungStephani Joy Y. MacalinoMinghua CuiJi Eon KimHye-Jin KimSeo Hee NamSemi KimSun ChoiJung Weon Lee
Keywords
amino acid transporter; arginine sensor; homology modeling; lysosome; metabolism; molecular docking modeling; mTOR; protein interaction; tetraspanin trafficking; TM4SF5
Issue Date
2019-06
Publisher
Cell metabolism
Citation
VOL 29, NO 6-1319
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.
URI
http://pubs.kist.re.kr/handle/201004/69492
ISSN
1550-4131
Appears in Collections:
KIST Publication > Article
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