Autophagy termination and lysosome reformation regulated by mTOR

By Li Yu, C. McPhee, Lixin Zheng, G. Mardones, Yueguang Rong, Junya Peng, Na Mi, Ying Zhao, Zhihua Liu, F. Wan and 5 more. Nature, 2010

1,396 citations recorded by the source corpus.

Autophagy is an evolutionarily conserved process by which cytoplasmic proteins and organelles are catabolized. During starvation, the protein TOR (target of rapamycin), a nutrient-responsive kinase, is inhibited, and this induces autophagy. In autophagy, double-membrane autophagosomes envelop and sequester intracellular components and then fuse with lysosomes to form autolysosomes, which degrade their contents to regenerate nutrients. Current models of autophagy terminate with the degradation of the autophagosome cargo in autolysosomes, but the regulation of autophagy in response to nutrients and the subsequent fate of the autolysosome are poorly understood. Here we show that mTOR signalling in rat kidney cells is inhibited during initiation of autophagy, but reactivated by prolonged starvation. Reactivation of mTOR is autophagy-dependent and requires the degradation of autolysosomal products. Increased mTOR activity attenuates autophagy and generates proto-lysosomal tubules and vesicles that extrude from autolysosomes and ultimately mature into functional lysosomes, thereby restoring the full complement of lysosomes in the cell—a process we identify in multiple animal species. Thus, an evolutionarily conserved cycle in autophagy governs nutrient sensing and lysosome homeostasis during starvation.

Subfields: Epidemiology, Pathology and Forensic Medicine, Pharmacology

View Paper: https://www.semanticscholar.org/paper/3b8439c6c7b3f8f3589d35650698a82544301e8d

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In Epidemiology

1. Beth Levine
2. D. Klionsky
3. N. Mizushima
4. Guido Kroemer
5. I. Slaninová
6. V. Deretic
7. Alec C. Kimmelman
8. D. Rubinsztein

In Pathology and Forensic Medicine

1. David M. Sabatini
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In Pharmacology

1. Beth Levine
2. N. Mizushima
3. Alec C. Kimmelman
4. D. Klionsky
5. M. Komatsu
6. T. Johansen
7. Guido Kroemer
8. V. Deretic

Citations in the corpus

• The mTOR Signalling Pathway in Human Cancer (2012, background): “autophagic degradation leads to the reactivation of mTORC1 and to the restoration of the cellular lysosomal population [110].”
• Regulation of Immune Responses by mTOR (2011, background): “Indeed, mTORC1 inhibition leads to an increase in autophagy, whereas mitochondrial biosynthesis is enhanced in the setting of increased mTORC1 activation (39, 40).”
• MTORC1 functions as a transcriptional regulator of autophagy by preventing nuclear transport of TFEB (2012, background): “suggest that this process may be implicated in reformation of lysosomes from autophagosomes following MTORC1 reactivation.(28) However, we observe redistribution of TFEB to the nucleus just 30 min after MTORC1 inactivation, a time at which autolysosomes formation and MTORC1 reactivation has not yet ”
• mTOR: from growth signal integration to cancer, diabetes and ageing (2010, background): “Thus, the flow of amino acids, glucose and other metabolites that are released by autophagy feeds back onto mTORC1, causing its partial reactivatio”
• Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, background): “…and acts in initiation of phagophore formation (Shibutani and Yoshimori, 2014) as well as in later steps of autophagosome maturation (Carlsson and Simonsen, 2015), including autophagosome-lysosome fusion (Ikonomov et al., 2006) and lysosome reformation (Rong et al., 2012; Yu et al., 2010).”
• Lysosomal membrane permeabilization and cell death (2018, background): “Lysosomes can also be regenerated via a process called autophagic lysosome reformation (ALR).(13) During autophagy, double-membrane autophagosomes containing intracellular components fuse with lysosomes to form autolysosomes, in which the sequestered contents are degraded.”
• Autophagy pathway: Cellular and molecular mechanisms (2018, background): “Adding rapamycin after autolysosome formation blocks ALR, and adding serum to starved cells causes activation of mTOR and initiation of ALR.71 In cells undergoing serum or glutamine starvation, which mimics in vivo starvation in a more physiologically relevant way, prolonged nutrient withdrawal caus”
• Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks (2011, background): “This in turn results in a slow-down of the autophagic machinery (118).”
• Autophagy: Renovation of Cells and Tissues (2011, background): “Restoration of cellular (or local) levels of amino acids reactivates the serine/threonine protein kinase mTORC1 (mammalian target of rapamycin complex 1) and terminates autophagy (Yu et al., 2010).”
• Lysosomal Physiology (2015, background): “Nutrient starvation not only inhibits mTOR-mediated growth, but also increases autophagosome (AP) formation (7).”