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Title 

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

Authors 

J W JungS J Y MacalinoM CuiJ E KimH J KimD G SongS H NamSemi KimS ChoiJ W Lee

Publisher 

Elsevier (Cell Press)

Issue Date 

2019

Citation 

Cell Metabolism

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 

https://doi.org/10.1016/j.cmet.2019.03.005

ISSN 

1550-4131

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-07-10


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