A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress

Autor: Gábor Bánhegyi, Bence Hajdú, Orsolya Kapuy, Marianna Holczer, Tamás Lőrincz, András Szarka
Jazyk: angličtina
Rok vydání: 2019
Předmět:
autophagy
Autophagic Cell Death
Cellular homeostasis
Nutrient sensing
mTORC1
AMP-Activated Protein Kinases
Mechanistic Target of Rapamycin Complex 1
Tuberous Sclerosis Complex 1 Protein
Article
Catalysis
ampk
lcsh:Chemistry
Inorganic Chemistry
Downregulation and upregulation
Stress
Physiological
Tuberous Sclerosis Complex 2 Protein
mtor
Autophagy-Related Protein-1 Homolog
Humans
Physical and Theoretical Chemistry
lcsh:QH301-705.5
Molecular Biology
Spectroscopy
Feedback
Physiological
Chemistry
Organic Chemistry
Autophagy
Intracellular Signaling Peptides and Proteins
AMPK
systems biology
General Medicine
ULK1
double negative feedback
Computer Science Applications
Cell biology
Enzyme Activation
mTOR
HEK293 Cells
Proteostasis
lcsh:Biology (General)
lcsh:QD1-999
biological phenomena
cell phenomena
and immunity
Signal Transduction
Zdroj: International Journal of Molecular Sciences; Volume 20; Issue 22; Pages: 5543
International Journal of Molecular Sciences, Vol 20, Iss 22, p 5543 (2019)
International Journal of Molecular Sciences
ISSN: 1422-0067
DOI: 10.3390/ijms20225543
Popis: Cellular homeostasis is controlled by an evolutionary conserved cellular digestive process called autophagy. This mechanism is tightly regulated by the two sensor elements called mTORC1 and AMPK. mTORC1 is one of the master regulators of proteostasis, while AMPK maintains cellular energy homeostasis. AMPK is able to promote autophagy by phosphorylating ULK1, the key inducer of autophagosome formation, while mTORC1 downregulates the self-eating process via ULK1 under nutrient rich conditions. We claim that the feedback loops of the AMPK−mTORC1−ULK1 regulatory triangle guarantee the appropriate response mechanism when nutrient and/or energy supply changes. In our opinion, there is an essential double negative feedback loop between mTORC1 and AMPK. Namely, not only does AMPK downregulate mTORC1, but mTORC1 also inhibits AMPK and this inhibition is required to keep AMPK inactive at physiological conditions. The aim of the present study was to explore the dynamical characteristic of AMPK regulation upon various cellular stress events. We approached our scientific analysis from a systems biology perspective by incorporating both theoretical and molecular biological techniques. In this study, we confirmed that AMPK is essential to promote autophagy, but is not sufficient to maintain it. AMPK activation is followed by ULK1 induction, where protein has a key role in keeping autophagy active. ULK1-controlled autophagy is always preceded by AMPK activation. With both ULK1 depletion and mTORC1 hyper-activation (i.e., TSC1/2 downregulation), we demonstrate that a double negative feedback loop between AMPK and mTORC1 is crucial for the proper dynamic features of the control network. Our computer simulations have further proved the dynamical characteristic of AMPK−mTORC1−ULK1 controlled cellular nutrient sensing.
Databáze: OpenAIRE
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