Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1

Szymańska, Paulina; Martin, Katie R.; MacKeigan, Jeffrey P.; Hlavacek, William S.; Lipniacki, Tomasz

doi:10.1371/journal.pone.0116550

Title: Computational analysis of an autophagy/translation switch based on mutual inhibition of MTORC1 and ULK1

Journal Article · Wed Mar 11 00:00:00 EDT 2015 · PLoS ONE

DOI:https://doi.org/10.1371/journal.pone.0116550· OSTI ID:1190538

Szymańska, Paulina ^[1]; Martin, Katie R. ^[2]; MacKeigan, Jeffrey P. ^[2]; Hlavacek, William S. ^[3]; Lipniacki, Tomasz ^[4]

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)

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.

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Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC52-06NA25396

OSTI ID:: 1190538

Journal Information:: PLoS ONE, Vol. 10, Issue 3; ISSN 1932-6203

Publisher:: Public Library of ScienceCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 29 works

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