1. Prolonged glutamine starvation reactivates mTOR to inhibit autophagy and initiate autophagic lysosome reformation to maintain cell viability.
- Author
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Singh A, Mahapatra KK, Praharaj PP, Patra S, Mishra SR, Patil S, and Bhutia SK
- Subjects
- Humans, rab7 GTP-Binding Proteins, rab GTP-Binding Proteins metabolism, rab GTP-Binding Proteins genetics, Cell Line, Tumor, Clathrin metabolism, Glutamine metabolism, Glutamine deficiency, Lysosomes metabolism, Lysosomes drug effects, Autophagy drug effects, TOR Serine-Threonine Kinases metabolism, Cell Survival drug effects
- Abstract
Autophagy, a cellular recycling mechanism, utilizes lysosomes for cellular degradation. Prolonged autophagy reduces the pool of functional lysosomes in the cell. However, lysosomal homeostasis is maintained through the regeneration of functional lysosomes during the terminal stage of autophagy, i.e. Autophagic lysosome reformation (ALR). Through confocal microscopy during glutamine starvation, we unravel the regeneration of tubules from autolysosomes by undertaking significant membrane remodeling, which majorly depends on mTOR reactivation, RAB7 dissociation, phosphatidyl inositol 3 phosphate (PI3P) dependent-dynamin 2 and clathrin recruitment. In glutamine-starved cells, we found mTOR is the central modulator in regulating ALR initiation, and its pharmacological inhibition with rapamycin leads to a decrease in lysosomal tubulation. Moreover, RAB7 and Clathrin are essential for tubule elongation and it showed that siRNA targeting RAB7 and Clathrin restricts tubule initiation under glutamine starvation. In this setting, we examined the physiological relevance of ALR during prolonged glutamine deprivation and found that genetic and pharmacological inhibition of critical proteins involved in ALR promotes cell death in oral cancer cells, establishing ALR is essential for maintaining cell survival during stress., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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