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

PloS One
Paulina SzymańskaTomasz Lipniacki

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 c...Continue Reading

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Citations

Aug 1, 2015·International Journal of Molecular Sciences·Bodo C Melnik
Jan 4, 2017·Scientific Reports·Marek KochańczykTomasz Lipniacki
Dec 16, 2017·Scientific Reports·Bing LiuIvet Bahar
May 12, 2018·Cell Death & Disease·Ji-Eun KimTae-Cheon Kang
Mar 2, 2016·PLoS Computational Biology·Beata HatTomasz Lipniacki
Sep 19, 2019·Interdisciplinary Sciences, Computational Life Sciences·Mohammadreza DorvashIman Tavassoly
May 21, 2017·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Wen ZhuCun-Zhi Liu
Nov 11, 2019·International Journal of Molecular Sciences·Marianna HolczerOrsolya Kapuy
Feb 7, 2019·Scientific Reports·Afroza ShirinFrancesco Sorrentino
Nov 7, 2019·World Journal of Stem Cells·Mohammadhossein Khorraminejad-ShiraziPouria Mosaddeghi
Sep 8, 2019·Journal of Theoretical Biology·Mohammadreza DorvashIman Tavassoly
Feb 4, 2021·Journal of Clinical Medicine·Adithya ChedereMohit Kumar Jolly
Sep 10, 2021·PLoS Computational Biology·Andrea TangherloniDaniela Besozzi

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Methods Mentioned

BETA
nuclear translocation
biosensor
GTPases
GTPase

Software Mentioned

BioNetGen
SUNDIALS
CVODE
MatCont
RuleBender
BNGL
AUTO

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