title: Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion.
abstract: Lysosome is a key subcellular organelle in the execution of the autophagic process and at present little is known whether lysosomal function is controlled in the process of autophagy. In this study, we first found that suppression of mammalian target of rapamycin (mTOR) activity by starvation or two mTOR catalytic inhibitors (PP242 and Torin1), but not by an allosteric inhibitor (rapamycin), leads to activation of lysosomal function. Second, we provided evidence that activation of lysosomal function is associated with the suppression of mTOR complex 1 (mTORC1), but not mTORC2, and the mTORC1 localization to lysosomes is not directly correlated to its regulatory role in lysosomal function. Third, we examined the involvement of transcription factor EB (TFEB) and demonstrated that TFEB activation following mTORC1 suppression is necessary but not sufficient for lysosomal activation. Finally, Atg5 or Atg7 deletion or blockage of the autophagosome-lysosome fusion process effectively diminished lysosomal activation, suggesting that lysosomal activation occurring in the course of autophagy is dependent on autophagosome-lysosome fusion. Taken together, this study demonstrates that in the course of autophagy, lysosomal function is upregulated via a dual mechanism involving mTORC1 suppression and autophagosome-lysosome fusion.
authors: Department of Physiology, Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597.
authors: Jing
authors: J
authors: Zhou
authors: Shi-Hao
authors: SH
authors: Tan
authors: Valérie
authors: V
authors: Nicolas
authors: Chantal
authors: C
authors: Bauvy
authors: Nai-Di
authors: ND
authors: Yang
authors: Jianbin
authors: J
authors: Zhang
authors: Yuan
authors: Y
authors: Xue
authors: Patrice
authors: P
authors: Codogno
authors: Han-Ming
authors: HM
authors: Shen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008247:Lysosomes / Q000187:drug effects* / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008561:Membrane Fusion / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology; D010588:Phagosomes / Q000187:drug effects* / Q000235:genetics; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007211:Indoles; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D009287:Naphthyridines; D011687:Purines; C064972:TFEB protein, human; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; C572919:PP242; D020123:Sirolimus