Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1
Abstract
We constructed a mechanistic, computational model for regulation of (macro)autophagy and protein synthesis (at the level of translation). The model was formulated to study the system-level consequences of interactions among the following proteins: two key components of MTOR complex 1 (MTORC1), namely the protein kinase MTOR (mechanistic target of rapamycin) and the scaffold protein RPTOR; the autophagy-initiating protein kinase ULK1; and the multimeric energy-sensing AMP-activated protein kinase (AMPK). Inputs of the model include intrinsic AMPK kinase activity, which is taken as an adjustable surrogate parameter for cellular energy level or AMP:ATP ratio, and rapamycin dose, which controls MTORC1 activity. Outputs of the model include the phosphorylation level of the translational repressor EIF4EBP1, a substrate of MTORC1, and the phosphorylation level of AMBRA1 (activating molecule in BECN1-regulated autophagy), a substrate of ULK1 critical for autophagosome formation. The model incorporates reciprocal regulation of mTORC1 and ULK1 by AMPK, mutual inhibition of MTORC1 and ULK1, and ULK1-mediated negative feedback regulation of AMPK. Through analysis of the model, we find that these processes may be responsible, depending on conditions, for graded responses to stress inputs, for bistable switching between autophagy and protein synthesis, or relaxation oscillations, comprising alternating periods of autophagy and protein synthesis.more »
- Authors:
-
- Univ. of Warsaw, Warsaw (Poland)
- Van Andel Research Inst. (VARI), Grand Rapids, MI (United States)
- Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- Institute of Fundamental Technological Research, Warsaw (Poland)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1190538
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- PLoS ONE
- Additional Journal Information:
- Journal Volume: 10; Journal Issue: 3; Journal ID: ISSN 1932-6203
- Publisher:
- Public Library of Science
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Szymańska, Paulina, Martin, Katie R., MacKeigan, Jeffrey P., Hlavacek, William S., and Lipniacki, Tomasz. Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1. United States: N. p., 2015.
Web. doi:10.1371/journal.pone.0116550.
Szymańska, Paulina, Martin, Katie R., MacKeigan, Jeffrey P., Hlavacek, William S., & Lipniacki, Tomasz. Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1. United States. https://doi.org/10.1371/journal.pone.0116550
Szymańska, Paulina, Martin, Katie R., MacKeigan, Jeffrey P., Hlavacek, William S., and Lipniacki, Tomasz. Wed .
"Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1". United States. https://doi.org/10.1371/journal.pone.0116550. https://www.osti.gov/servlets/purl/1190538.
@article{osti_1190538,
title = {Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1},
author = {Szymańska, Paulina and Martin, Katie R. and MacKeigan, Jeffrey P. and Hlavacek, William S. and Lipniacki, Tomasz},
abstractNote = {We constructed a mechanistic, computational model for regulation of (macro)autophagy and protein synthesis (at the level of translation). The model was formulated to study the system-level consequences of interactions among the following proteins: two key components of MTOR complex 1 (MTORC1), namely the protein kinase MTOR (mechanistic target of rapamycin) and the scaffold protein RPTOR; the autophagy-initiating protein kinase ULK1; and the multimeric energy-sensing AMP-activated protein kinase (AMPK). Inputs of the model include intrinsic AMPK kinase activity, which is taken as an adjustable surrogate parameter for cellular energy level or AMP:ATP ratio, and rapamycin dose, which controls MTORC1 activity. Outputs of the model include the phosphorylation level of the translational repressor EIF4EBP1, a substrate of MTORC1, and the phosphorylation level of AMBRA1 (activating molecule in BECN1-regulated autophagy), a substrate of ULK1 critical for autophagosome formation. The model incorporates reciprocal regulation of mTORC1 and ULK1 by AMPK, mutual inhibition of MTORC1 and ULK1, and ULK1-mediated negative feedback regulation of AMPK. Through analysis of the model, we find that these processes may be responsible, depending on conditions, for graded responses to stress inputs, for bistable switching between autophagy and protein synthesis, or relaxation oscillations, comprising alternating periods of autophagy and protein synthesis. A sensitivity analysis indicates that the prediction of oscillatory behavior is robust to changes of the parameter values of the model. The model provides testable predictions about the behavior of the AMPK-MTORC1-ULK1 network, which plays a central role in maintaining cellular energy and nutrient homeostasis.},
doi = {10.1371/journal.pone.0116550},
journal = {PLoS ONE},
number = 3,
volume = 10,
place = {United States},
year = {Wed Mar 11 00:00:00 EDT 2015},
month = {Wed Mar 11 00:00:00 EDT 2015}
}
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- Holczer, Marianna; Hajdú, Bence; Lőrincz, Tamás
- International Journal of Molecular Sciences, Vol. 20, Issue 22
A Systems Biology Roadmap to Decode mTOR Control System in Cancer
journal, September 2019
- Dorvash, Mohammadreza; Farahmandnia, Mohammad; Tavassoly, Iman
- Interdisciplinary Sciences: Computational Life Sciences, Vol. 12, Issue 1
Breaking Therapy Resistance: An Update on Oncolytic Newcastle Disease Virus for Improvements of Cancer Therapy
journal, August 2019
- Schirrmacher, Volker; van Gool, Stefaan; Stuecker, Wilfried
- Biomedicines, Vol. 7, Issue 3, p. 66
Quantitative assessment of cell fate decision between autophagy and apoptosis
journal, December 2017
- Liu, Bing; Oltvai, Zoltán N.; Bayır, Hülya
- Scientific Reports, Vol. 7, Issue 1
Mechanisms of Acupuncture Therapy for Cerebral Ischemia: an Evidence-Based Review of Clinical and Animal Studies on Cerebral Ischemia
journal, May 2017
- Zhu, Wen; Ye, Yang; Liu, Yi
- Journal of Neuroimmune Pharmacology, Vol. 12, Issue 4
P2RX7-MAPK1/2-SP1 axis inhibits MTOR independent HSPB1-mediated astroglial autophagy
journal, May 2018
- Kim, Ji-Eun; Ko, Ah-Reum; Hyun, Hye-Won
- Cell Death & Disease, Vol. 9, Issue 5
Prediction of Optimal Drug Schedules for Controlling Autophagy
journal, February 2019
- Shirin, Afroza; Klickstein, Isaac S.; Feng, Song
- Scientific Reports, Vol. 9, Issue 1
Ribosome profiling reveals translational regulation of mammalian cells in response to hypoxic stress
journal, August 2017
- Jiang, Zhiwen; Yang, Jiaqi; Dai, Aimei
- BMC Genomics, Vol. 18, Issue 1
AICAR and nicotinamide treatment synergistically augment the proliferation and attenuate senescence-associated changes in mesenchymal stromal cells
journal, February 2020
- Khorraminejad-Shirazi, Mohammadhossein; Sani, Mahsa; Talaei-Khozani, Tahereh
- Stem Cell Research & Therapy, Vol. 11, Issue 1
Feedbacks, Bifurcations, and Cell Fate Decision-Making in the p53 System
journal, February 2016
- Hat, Beata; Kochańczyk, Marek; Bogdał, Marta N.
- PLOS Computational Biology, Vol. 12, Issue 2
Breaking Therapy Resistance: An Update on Oncolytic Newcastle Disease Virus for Improvements of Cancer Therapy
journal, August 2019
- Schirrmacher, Volker; van Gool, Stefaan; Stuecker, Wilfried
- Biomedicines, Vol. 7, Issue 3, p. 66
Milk—A Nutrient System of Mammalian Evolution Promoting mTORC1-Dependent Translation
journal, July 2015
- Melnik, Bodo
- International Journal of Molecular Sciences, Vol. 16, Issue 8
Electroacupuncture protects against ischemic stroke by reducing autophagosome formation and inhibiting autophagy through the mTORC1-ULK1 complex-Beclin1 pathway
journal, December 2015
- Liu, Weilin; Shang, Guanhao; Yang, Shanli
- International Journal of Molecular Medicine, Vol. 37, Issue 2
Aging: A cell source limiting factor in tissue engineering
journal, October 2019
- Khorraminejad-Shirazi, Mohammadhossein; Dorvash, Mohammadreza; Estedlal, Alireza
- World J Stem Cells, Vol. 11, Issue 10