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

Szymańska P, Martin KR, MacKeigan JP, Hlavacek WS, Lipniacki T - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.

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.

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Results from bifurcation analysis of the system with negative feedback from ULK1 to AMPK.The solid blue curves indicate stable steady-state levels of AMBRA1 phosphorylation for (A) different levels of AMPK* and (B) different levels of rapamycin*. The dotted curves indicate lower and upper bounds of stable limit cycles. The red curves indicate periods of oscillation (see right vertical axes). In the left panel, the level of rapamycin* is held fixed at zero. In the right panel, the level of AMPK* is held fixed at 30,000 copies per cell. For both panels, the parameters considered in Table 1 are held fixed at their nominal values. The labels SNIC1 and SNIC2 indicate saddle-node-on-invariant-circle bifurcation points, and the label SuperH indicates a supercritical Hopf bifurcation point. The labels SubH and CF refer to subcritical Hopf and cyclic fold bifurcation points, which are very close to each other (panel A).
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pone.0116550.g005: Results from bifurcation analysis of the system with negative feedback from ULK1 to AMPK.The solid blue curves indicate stable steady-state levels of AMBRA1 phosphorylation for (A) different levels of AMPK* and (B) different levels of rapamycin*. The dotted curves indicate lower and upper bounds of stable limit cycles. The red curves indicate periods of oscillation (see right vertical axes). In the left panel, the level of rapamycin* is held fixed at zero. In the right panel, the level of AMPK* is held fixed at 30,000 copies per cell. For both panels, the parameters considered in Table 1 are held fixed at their nominal values. The labels SNIC1 and SNIC2 indicate saddle-node-on-invariant-circle bifurcation points, and the label SuperH indicates a supercritical Hopf bifurcation point. The labels SubH and CF refer to subcritical Hopf and cyclic fold bifurcation points, which are very close to each other (panel A).

Mentions: To further investigate this behavior, we performed a bifurcation analysis (Fig. 5). We found stable steady states and stable limit cycles of the system at different levels of AMPK* (Fig. 5A) and at different levels of rapamycin* (Fig. 5B). Our results, interpreted using bifurcation theory [25], reveal the qualitative behavior of the system.


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

Szymańska P, Martin KR, MacKeigan JP, Hlavacek WS, Lipniacki T - PLoS ONE (2015)

Results from bifurcation analysis of the system with negative feedback from ULK1 to AMPK.The solid blue curves indicate stable steady-state levels of AMBRA1 phosphorylation for (A) different levels of AMPK* and (B) different levels of rapamycin*. The dotted curves indicate lower and upper bounds of stable limit cycles. The red curves indicate periods of oscillation (see right vertical axes). In the left panel, the level of rapamycin* is held fixed at zero. In the right panel, the level of AMPK* is held fixed at 30,000 copies per cell. For both panels, the parameters considered in Table 1 are held fixed at their nominal values. The labels SNIC1 and SNIC2 indicate saddle-node-on-invariant-circle bifurcation points, and the label SuperH indicates a supercritical Hopf bifurcation point. The labels SubH and CF refer to subcritical Hopf and cyclic fold bifurcation points, which are very close to each other (panel A).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4356596&req=5

pone.0116550.g005: Results from bifurcation analysis of the system with negative feedback from ULK1 to AMPK.The solid blue curves indicate stable steady-state levels of AMBRA1 phosphorylation for (A) different levels of AMPK* and (B) different levels of rapamycin*. The dotted curves indicate lower and upper bounds of stable limit cycles. The red curves indicate periods of oscillation (see right vertical axes). In the left panel, the level of rapamycin* is held fixed at zero. In the right panel, the level of AMPK* is held fixed at 30,000 copies per cell. For both panels, the parameters considered in Table 1 are held fixed at their nominal values. The labels SNIC1 and SNIC2 indicate saddle-node-on-invariant-circle bifurcation points, and the label SuperH indicates a supercritical Hopf bifurcation point. The labels SubH and CF refer to subcritical Hopf and cyclic fold bifurcation points, which are very close to each other (panel A).
Mentions: To further investigate this behavior, we performed a bifurcation analysis (Fig. 5). We found stable steady states and stable limit cycles of the system at different levels of AMPK* (Fig. 5A) and at different levels of rapamycin* (Fig. 5B). Our results, interpreted using bifurcation theory [25], reveal the qualitative behavior of the system.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: College of Inter-Faculty Individual Studies in Mathematics and Natural Sciences, University of Warsaw, Warsaw, Poland.

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.

Show MeSH