Pu Jing, Keren-Kaplan Tal, Bonifacino Juan S
Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.
Cell Biology and Neurobiology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
J Cell Biol. 2017 Dec 4;216(12):4183-4197. doi: 10.1083/jcb.201703094. Epub 2017 Oct 9.
Lysosomes play key roles in the cellular response to amino acid availability. Depletion of amino acids from the medium turns off a signaling pathway involving the Ragulator complex and the Rag guanosine triphosphatases (GTPases), causing release of the inactive mammalian target of rapamycin complex 1 (mTORC1) serine/threonine kinase from the lysosomal membrane. Decreased phosphorylation of mTORC1 substrates inhibits protein synthesis while activating autophagy. Amino acid depletion also causes clustering of lysosomes in the juxtanuclear area of the cell, but the mechanisms responsible for this phenomenon are poorly understood. Herein we show that Ragulator directly interacts with BLOC-1-related complex (BORC), a multi-subunit complex previously found to promote lysosome dispersal through coupling to the small GTPase Arl8 and the kinesins KIF1B and KIF5B. Interaction with Ragulator exerts a negative regulatory effect on BORC that is independent of mTORC1 activity. Amino acid depletion strengthens this interaction, explaining the redistribution of lysosomes to the juxtanuclear area. These findings thus demonstrate that amino acid availability controls lysosome positioning through Ragulator-dependent, but mTORC1-independent, modulation of BORC.
溶酶体在细胞对氨基酸可用性的反应中发挥关键作用。培养基中氨基酸的耗尽会关闭一条涉及Ragulator复合物和Rag鸟苷三磷酸酶（GTP酶）的信号通路，导致无活性的雷帕霉素复合物1（mTORC1）丝氨酸/苏氨酸激酶从溶酶体膜上释放。mTORC1底物磷酸化的减少会抑制蛋白质合成，同时激活自噬。氨基酸耗尽还会导致溶酶体在细胞近核区域聚集，但导致这种现象的机制尚不清楚。在此我们表明，Ragulator直接与BLOC-1相关复合物（BORC）相互作用，BORC是一种先前发现的多亚基复合物，通过与小GTP酶Arl8以及驱动蛋白KIF1B和KIF5B偶联来促进溶酶体分散。与Ragulator的相互作用对BORC产生负调控作用，且这种作用独立于mTORC1活性。氨基酸耗尽会增强这种相互作用，解释了溶酶体重新分布到近核区域的现象。因此，这些发现表明氨基酸可用性通过Ragulator依赖性但mTORC1非依赖性的BORC调节来控制溶酶体定位。
