Oscillatory autophagy induction is enabled by an updated AMPK-ULK1 regulatory wiring

Autophagy-dependent survival relies on a crucial oscillatory response during cellular stress. Although oscillatory behaviour is typically associated with processes like the cell cycle or circadian rhythm, emerging experimental and theoretical evidence suggests that such periodic dynamics may explain...

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Bibliographic Details
Published in:PloS one 2024-12, Vol.19 (12), p.e0313302
Main Authors: Kapuy, Orsolya, Holczer, Marianna, Csabai, Luca, Korcsmáros, Tamás
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases - metabolism
Animals
Autophagy
Autophagy - physiology
Autophagy-Related Protein-1 Homolog - genetics
Autophagy-Related Protein-1 Homolog - metabolism
Biological effects
Biology and Life Sciences
Cell cycle
Cell death
Cell survival
Circadian rhythms
Computer and Information Sciences
Engineering and Technology
Feedback loops
Feedback, Physiological
Humans
Intracellular Signaling Peptides and Proteins - genetics
Intracellular Signaling Peptides and Proteins - metabolism
Kinases
Mechanistic Target of Rapamycin Complex 1 - metabolism
Models, Biological
Ordinary differential equations
Physical Sciences
Positive feedback
Proteins
Signal Transduction
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Summary:Autophagy-dependent survival relies on a crucial oscillatory response during cellular stress. Although oscillatory behaviour is typically associated with processes like the cell cycle or circadian rhythm, emerging experimental and theoretical evidence suggests that such periodic dynamics may explain conflicting experimental results in autophagy research. In this study, we demonstrate that oscillatory behaviour in the regulation of the non-selective, stress-induced macroautophagy arises from a series of interlinked negative and positive feedback loops within the mTORC1-AMPK-ULK1 regulatory triangle. While many of these interactions have been known for decades, recent discoveries have revealed how mTORC1, AMPK, and ULK1 are truly interconnected. Although these new findings initially appeared contradictory to established models, additional experiments and our systems biology analysis clarify the updated regulatory structure. Through computational modelling of the autophagy oscillatory response, we show how this regulatory network governs autophagy induction. Our results not only reconcile previous conflicting experimental observations but also offer insights for refining autophagy regulation and advancing understanding of its mechanisms of action.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0313302