Volume 23, No 4, Apr 2013
ISSN: 1001-0602
EISSN: 1748-7838 2018
impact factor 17.848*
(Clarivate Analytics, 2019)
Volume 23 Issue 4, April 2013: 508-523
ORIGINAL ARTICLES
Activation of lysosomal function in the course of autophagy via mTORC1 suppression and autophagosome-lysosome fusion
Jing Zhou1, Shi-Hao Tan1,2, Valérie Nicolas3,4, Chantal Bauvy4,5, Nai-Di Yang1, Jianbin Zhang 1, Yuan Xue6, Patrice Codogno4,5 and Han-Ming Shen1,2
1Department of Physiology, Yong Loo Lin School of Medicine and Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597
2NUS Graduate School for Integrative Sciences and Engineering National University of Singapore, Singapore 117597
3Microscopy Facility-IFR-141-IPSIT, rue JB Clément, 92296 Châtenay-Malabry, France
4University Paris-Sud, Orsay, France
5INSERM U984, 92296 Châtenay-Malabry, France
6Reed College, Portland, OR 97202, USA
Correspondence: Han-Ming Shen,(han-ming_shen@nuhs.edu.sg)
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.
Cell Research (2013) 23:508–523. doi:10.1038/cr.2013.11; published online 22 January 2013
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