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Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study

One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillat...

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Autores principales: Hajdú, Bence, Csabai, Luca, Márton, Margita, Holczer, Marianna, Korcsmáros, Tamás, Kapuy, Orsolya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10143760/
https://www.ncbi.nlm.nih.gov/pubmed/37108830
http://dx.doi.org/10.3390/ijms24087671
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author Hajdú, Bence
Csabai, Luca
Márton, Margita
Holczer, Marianna
Korcsmáros, Tamás
Kapuy, Orsolya
author_facet Hajdú, Bence
Csabai, Luca
Márton, Margita
Holczer, Marianna
Korcsmáros, Tamás
Kapuy, Orsolya
author_sort Hajdú, Bence
collection PubMed
description One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulatory triangle. Here, we introduce a systems biology analysis to explain in detail the dynamical features of the essential negative and double-negative feedback loops and also the periodic repeat of autophagy induction upon cellular stress. We propose an additional regulatory molecule in the autophagy control network that delays some of AMPK’s effect on the system, making the model output more consistent with experimental results. Furthermore, a network analysis on AutophagyNet was carried out to identify which proteins could be the proposed regulatory components in the system. These regulatory proteins should satisfy the following rules: (1) they are induced by AMPK; (2) they promote ULK1; (3) they down-regulate mTOR upon cellular stress. We have found 16 such regulatory components that have been experimentally proven to satisfy at least two of the given rules. Identifying such critical regulators of autophagy induction could support anti-cancer- and ageing-related therapeutic efforts.
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spelling pubmed-101437602023-04-29 Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study Hajdú, Bence Csabai, Luca Márton, Margita Holczer, Marianna Korcsmáros, Tamás Kapuy, Orsolya Int J Mol Sci Article One of the main inducers of autophagy-dependent self-cannibalism, called ULK1, is tightly regulated by the two sensor molecules of nutrient conditions and energy status, known as mTOR and AMPK kinases, respectively. Recently, we developed a freely available mathematical model to explore the oscillatory characteristic of the AMPK-mTOR-ULK1 regulatory triangle. Here, we introduce a systems biology analysis to explain in detail the dynamical features of the essential negative and double-negative feedback loops and also the periodic repeat of autophagy induction upon cellular stress. We propose an additional regulatory molecule in the autophagy control network that delays some of AMPK’s effect on the system, making the model output more consistent with experimental results. Furthermore, a network analysis on AutophagyNet was carried out to identify which proteins could be the proposed regulatory components in the system. These regulatory proteins should satisfy the following rules: (1) they are induced by AMPK; (2) they promote ULK1; (3) they down-regulate mTOR upon cellular stress. We have found 16 such regulatory components that have been experimentally proven to satisfy at least two of the given rules. Identifying such critical regulators of autophagy induction could support anti-cancer- and ageing-related therapeutic efforts. MDPI 2023-04-21 /pmc/articles/PMC10143760/ /pubmed/37108830 http://dx.doi.org/10.3390/ijms24087671 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hajdú, Bence
Csabai, Luca
Márton, Margita
Holczer, Marianna
Korcsmáros, Tamás
Kapuy, Orsolya
Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study
title Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study
title_full Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study
title_fullStr Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study
title_full_unstemmed Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study
title_short Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study
title_sort oscillation of autophagy induction under cellular stress and what lies behind it, a systems biology study
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10143760/
https://www.ncbi.nlm.nih.gov/pubmed/37108830
http://dx.doi.org/10.3390/ijms24087671
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