LAPTM4b将LAT1-4F2hc亮氨酸转运体招募至溶酶体并促进mTORC1激活。
LAPTM4b recruits the LAT1-4F2hc Leu transporter to lysosomes and promotes mTORC1 activation.
作者信息
Milkereit Ruth, Persaud Avinash, Vanoaica Liviu, Guetg Adriano, Verrey Francois, Rotin Daniela
机构信息
Program in Cell Biology, The Hospital for Sick Children, Biochemistry Department, University of Toronto, Toronto, Ontario M5G 0A4, Canada.
Center for Integrative Human Physiology (ZIHP) and NCCR Kidney, Institute of Physiology, University of Zurich, Zurich 8057, Switzerland.
出版信息
Nat Commun. 2015 May 22;6:7250. doi: 10.1038/ncomms8250.
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.
雷帕霉素哺乳动物靶蛋白1（mTORC1）是细胞生长的主要调节因子，在生长因子、能量信号以及细胞内必需氨基酸（如亮氨酸）下游被激活。mTORC1的激活发生在溶酶体膜上，涉及溶酶体内必需氨基酸对V-ATP酶的刺激（由内而外激活），通过Rheb-GTP导致Ragulator、RagA/B-GTP和mTORC1的激活。亮氨酸如何进入溶酶体尚不清楚。在这里，我们鉴定出溶酶体蛋白LAPTM4b是亮氨酸转运体LAT1-4F2hc（SLC7A5-SLAC3A2）的结合伴侣。我们发现LAPTM4b将LAT1-4F2hc招募到溶酶体，导致亮氨酸摄取到溶酶体中，并且在必需氨基酸或亮氨酸刺激后通过V-ATP酶激活mTORC1时是必需的。这些结果证明了溶酶体上存在功能性亮氨酸转运体，并有助于解释亮氨酸/必需氨基酸对mTORC1的由内而外的溶酶体激活作用。
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