Open Access
International Journal of Molecular Sciences, volume 20, issue 22, pages 5543
A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress
Holczer Marianna
1
,
Hajdú Bence
1
,
Lőrincz Tamás
2
,
Szarka András
2
,
BÁNHEGYI Gábor
1, 3
,
Kapuy Orsolya
1
1
Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1085 Budapest, Hungary
|
2
Laboratory of Biochemistry and Molecular Biology, Department of Applied Biotechnology and Food Science, Budapest University of Technology and Economics, 1111 Budapest, Hungary
|
3
Pathobiochemistry Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1085 Budapest, Hungary
|
Publication type: Journal Article
Publication date: 2019-11-07
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor: 5.6
ISSN: 16616596, 14220067
PubMed ID:
31703252
Catalysis
Organic Chemistry
Inorganic Chemistry
Physical and Theoretical Chemistry
Computer Science Applications
Spectroscopy
Molecular Biology
General Medicine
Abstract
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.
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- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
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Holczer M. et al. A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress // International Journal of Molecular Sciences. 2019. Vol. 20. No. 22. p. 5543.
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Holczer M., Hajdú B., Lőrincz T., Szarka A., BÁNHEGYI G., Kapuy O. A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress // International Journal of Molecular Sciences. 2019. Vol. 20. No. 22. p. 5543.
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TY - JOUR
DO - 10.3390/ijms20225543
UR - https://doi.org/10.3390%2Fijms20225543
TI - A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress
T2 - International Journal of Molecular Sciences
AU - Holczer, Marianna
AU - Hajdú, Bence
AU - Szarka, András
AU - BÁNHEGYI, Gábor
AU - Kapuy, Orsolya
AU - Lőrincz, Tamás
PY - 2019
DA - 2019/11/07 00:00:00
PB - Multidisciplinary Digital Publishing Institute (MDPI)
SP - 5543
IS - 22
VL - 20
PMID - 31703252
SN - 1661-6596
SN - 1422-0067
ER -
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@article{2019_Holczer,
author = {Marianna Holczer and Bence Hajdú and András Szarka and Gábor BÁNHEGYI and Orsolya Kapuy and Tamás Lőrincz},
title = {A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress},
journal = {International Journal of Molecular Sciences},
year = {2019},
volume = {20},
publisher = {Multidisciplinary Digital Publishing Institute (MDPI)},
month = {nov},
url = {https://doi.org/10.3390%2Fijms20225543},
number = {22},
pages = {5543},
doi = {10.3390/ijms20225543}
}
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MLA
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Holczer, Marianna, et al. “A Double Negative Feedback Loop between mTORC1 and AMPK Kinases Guarantees Precise Autophagy Induction upon Cellular Stress.” International Journal of Molecular Sciences, vol. 20, no. 22, Nov. 2019, p. 5543. https://doi.org/10.3390%2Fijms20225543.