Image from Nature Communications paper,
Milkereit R*, Persaud A*, Vanoaica L, Guetg A, Verrey F, ROTIN D. LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation. Nature Communications. 6: 7250 doi. 10:1038/ncomms8250 (2015) (*Equal contribution)
Mammalian Target of Rapamycin Complex 1 (mTORC1) is a master regulator of energy metabolism, protein synthesis, cell and animal growth, and it is implicated in numerous diseases, including cancer. Influx of essential amino acids such as Leu into cells is mediated by the LAT1-4F2hc (SLC7A5-SLC3A2) transporter in exchange for Gln, and results in the recruitment of the mTORC1 complex to the lysosomal membrane. Intracellular Leu then enters the lysosome to activate the lysosomal membrane protein H+ATPase (V-ATPase) from inside the lysosome (inside-out mechanism), leading to activation of mTORC1. The critical step of how Leu enters the lysosomes was unknown. Here, Ruth Milkereit and Avinash Persaud from the Rotin lab (and collaborators from the Verrey’s lab) discovered the missing link: they identified the lysosomal protein LAPTM4b as a binding partner for the Leu Transporter, LAT1-4F2hc. They then showed that LAPTM4b recruits LAT1-4F2hc to the lysosome, leading to uptake of Leu into this organelle and stimulation of mTORC1 activation via the H+-ATPase. These results provide the first demonstration of a functional Leu transporter at the lysosome, and help explain the inside-out lysosomal activation of mTORC1 by Leu.
