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LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation

Author

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  • Ruth Milkereit

    (Program in Cell Biology, The Hospital for Sick Children, University of Toronto)

  • Avinash Persaud

    (Program in Cell Biology, The Hospital for Sick Children, University of Toronto)

  • Liviu Vanoaica

    (Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich)

  • Adriano Guetg

    (Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich)

  • Francois Verrey

    (Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich)

  • Daniela Rotin

    (Program in Cell Biology, The Hospital for Sick Children, University of Toronto)

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.

Suggested Citation

  • Ruth Milkereit & Avinash Persaud & Liviu Vanoaica & Adriano Guetg & Francois Verrey & Daniela Rotin, 2015. "LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8250
    DOI: 10.1038/ncomms8250
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    1. Nick Huang & Thomas Winans & Brandon Wyman & Zachary Oaks & Tamas Faludi & Gourav Choudhary & Zhi-Wei Lai & Joshua Lewis & Miguel Beckford & Manuel Duarte & Daniel Krakko & Akshay Patel & Joy Park & T, 2024. "Rab4A-directed endosome traffic shapes pro-inflammatory mitochondrial metabolism in T cells via mitophagy, CD98 expression, and kynurenine-sensitive mTOR activation," Nature Communications, Nature, vol. 15(1), pages 1-26, December.
    2. Teena Bhakuni & Pieter R. Norden & Naoto Ujiie & Can Tan & Sun Kyong Lee & Thomas Tedeschi & Yi-Wen Hsieh & Ying Wang & Ting Liu & Amani A. Fawzi & Tsutomu Kume, 2024. "FOXC1 regulates endothelial CD98 (LAT1/4F2hc) expression in retinal angiogenesis and blood-retina barrier formation," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Yandan Yang & Arnold Bolomsky & Thomas Oellerich & Ping Chen & Michele Ceribelli & Björn Häupl & George W. Wright & James D. Phelan & Da Wei Huang & James W. Lord & Callie K. Winkle & Xin Yu & Jan Wis, 2022. "Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Di Wu & Renhong Yan & Siyuan Song & Andrew K. Swansiger & Yaning Li & James S. Prell & Qiang Zhou & Carol V. Robinson, 2024. "The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Liad Hinden & Majdoleen Ahmad & Sharleen Hamad & Alina Nemirovski & Gergő Szanda & Sandra Glasmacher & Aviram Kogot-Levin & Rinat Abramovitch & Bernard Thorens & Jürg Gertsch & Gil Leibowitz & Joseph , 2022. "Opposite physiological and pathological mTORC1-mediated roles of the CB1 receptor in regulating renal tubular function," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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