Lysosomal positioning coordinates cellular nutrient responses

By Viktor I. Korolchuk, S. Saiki, Maike Lichtenberg, Farah H. Siddiqi, Esteban A. Roberts, S. Imarisio, Luca Jahreiss, Sovan Sarkar, M. Futter, Fiona M Menzies and 3 more. Nature Cell Biology, 2011

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mTOR (mammalian target of rapamycin) 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 with 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, whereas starvation causes perinuclear clustering of lysosomes, driven by changes in intracellular pH. 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 at both the initiation and termination stages of the process. Our findings provide a physiological role for the dynamic state of lysosomal positioning in cells as a coordinator of mTORC1 signalling with autophagic flux.

Subfields: Cell Biology, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/0d91035e1036000892e1696a9129eb659df92c01

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Citations in the corpus

TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation (2012, neutral): “…adaptors (Bjørkøy et al., 2005; Thurston et al., 2009; Wild et al., 2011) and the less understood process of the maturation of autophagic organelles into autolysosomes, where the captured material is degraded (Korolchuk et al., 2011; Liang et al., 2008; Matsunaga et al., 2009; Zhong et al., 2009).”
Brief update on endocytosis of nanomedicines (2019, background): “Sequestration of nutrients in the lumen of peripheral lysosomes induces cell proliferation through the activation of the mechanistic target of rapamycin complex 1 (mTORCl) [57].”
Autophagy and aging. (2011, background): “This is essential for mTOR activation resulting in decreased autophagosome formation (Korolchuk et al., 2011).”
Lysosomal Physiology (2015, background): “In addition, lysosomes are redistributed to the perinuclear region, where AP-lysosome fusion primarily takes place (12).”
The lysosome: from waste bag to potential therapeutic target. (2013, background): “Lysosomes change their intracellular distribution in response to nutrient availability, from peripheral location at nutrient-rich conditions to perinuclear clustering during starvation (Korolchuk et al., 2011).”