Abstract:
: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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Korolchuk VI,Saiki S,Lichtenberg M,Siddiqi FH,Roberts EA,Imarisio S,Jahreiss L,Sarkar S,Futter M,Menzies FM,O'Kane CJ,Deretic V,Rubinsztein DCdoi
10.1038/ncb2204subject
Has Abstractpub_date
2011-04-01 00:00:00pages
453-60issue
4eissn
1465-7392issn
1476-4679pii
ncb2204journal_volume
13pub_type
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