title: 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. 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.
authors.affiliation: College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.
authors.forename: Paulina
authors.initials: P
authors.lastname: Szymańska
authors.affiliation: Van Andel Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Katie R
authors.initials: KR
authors.lastname: Martin
authors.affiliation: Van Andel Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: MacKeigan
authors.affiliation: Theoretical Division and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
authors.forename: William S
authors.initials: WS
authors.lastname: Hlavacek
authors.affiliation: Institute of Fundamental Technological Research, Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Lipniacki
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D018797:Cell Cycle Proteins; D019295:Computational Biology / Q000379:methods*; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008957:Models, Genetic; D046912:Multiprotein Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; D055372:AMP-Activated Protein Kinases; D020123:Sirolimus