Lysosomal positioning coordinates cellular nutrient responses.
Lysosomal positioning coordinates cellular nutrient responses.
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DOI：
10.1038/ncb2204
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发表时间：
2011-04
影响因子：
21.3
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中科院分区：
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哺乳动物雷帕霉素靶蛋白（mTOR）信号传导和巨自噬（此后称为自噬）调节许多病理和生理过程，包括对改变的营养水平的细胞反应。然而，调节mTOR和自噬的机制仍不完全清楚。溶酶体是动态的细胞内细胞器，密切参与mTOR复合物1（mTORC 1）信号传导的激活和降解自噬底物。在这里，我们报告说，溶酶体定位协调合成代谢和分解代谢反应的变化，营养物质的供应，通过精心策划早期质膜信号事件，mTORC 1信号和自噬。mTORC 1的激活与其存在于物理上接近上游信号模块的外周溶酶体相关，而饥饿导致溶酶体的核周聚集，由细胞内pH值（pHi）的变化驱动。溶酶体定位调节mTORC 1信号传导，这反过来又影响自噬体的形成。溶酶体定位也影响自噬体-溶酶体融合速率，从而通过作用于该过程的起始和终止阶段来控制自噬通量。我们的研究结果提供了一个基本的生理作用的动态溶酶体定位在细胞中作为一个协调员的mTORC 1信号与自噬通量。
Mammalian target of rapamycin (mTOR) signalling and macroautophagy (henceforth autophagy) regulate numerous pathological and physiological processes including cellular responses to altered nutrient levels. However, the mechanisms regulating mTOR and autophagy remain incompletely understood. Lysosomes are dynamic intracellular organelles intimately involved both in the activation of mTOR complex 1 (mTORC1) signalling and in degrading autophagic substrates. Here we report that lysosomal positioning coordinates anabolic and catabolic responses to changes in nutrient availability by orchestrating early plasma membrane signalling events, mTORC1 signalling and autophagy. Activation of mTORC1 by nutrients correlates with its presence on peripheral lysosomes that are physically close to the upstream signalling modules, while starvation causes perinuclear clustering of lysosomes, driven by changes in intracellular pH (pHi). Lysosomal positioning regulates mTORC1 signalling, which, in turn, influences autophagosome formation. Lysosome positioning also influences autophagosome-lysosome fusion rates, and thus controls autophagic flux by acting both at the initiation and termination stages of the process. Our findings provide a fundamental physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux.