title: LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.
abstract: Mammalian target of rapamycin 1 (mTORC1), a master regulator of cellular growth, is activated downstream of growth factors, energy signalling and intracellular essential amino acids (EAAs) such as Leu. mTORC1 activation occurs at the lysosomal membrane, and involves V-ATPase stimulation by intra-lysosomal EAA (inside-out activation), leading to activation of the Ragulator, RagA/B-GTP and mTORC1 via Rheb-GTP. How Leu enters the lysosomes is unknown. Here we identified the lysosomal protein LAPTM4b as a binding partner for the Leu transporter, LAT1-4F2hc (SLC7A5-SLAC3A2). We show that LAPTM4b recruits LAT1-4F2hc to lysosomes, leading to uptake of Leu into lysosomes, and is required for mTORC1 activation via V-ATPase following EAA or Leu stimulation. These results demonstrate a functional Leu transporter at the lysosome, and help explain the inside-out lysosomal activation of mTORC1 by Leu/EAA.
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Biochemistry Department, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Ruth
authors.initials: R
authors.lastname: Milkereit
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Biochemistry Department, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Avinash
authors.initials: A
authors.lastname: Persaud
authors.affiliation: Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Liviu
authors.initials: L
authors.lastname: Vanoaica
authors.affiliation: Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Guetg
authors.affiliation: Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich, Zurich 8057, Switzerland.
authors.forename: Francois
authors.identifier: 0000000332509824
authors.initials: F
authors.lastname: Verrey
authors.affiliation: Program in Cell Biology, The Hospital for Sick Children, Biochemistry Department, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rotin
mesh_terms: D006367:HeLa Cells; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000378:metabolism*; D007930:Leucine / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008565:Membrane Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism
chemical_list: C477083:LAPTM4B protein, human; D027283:Large Neutral Amino Acid-Transporter 1; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D015513:Oncogene Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D025262:Vacuolar Proton-Translocating ATPases; D007930:Leucine