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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| Format: | Article |
| Language: | English |
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MDPI AG
2023-04-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/8/7671 |
| _version_ | 1797604986888126464 |
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| author | Bence Hajdú Luca Csabai Margita Márton Marianna Holczer Tamás Korcsmáros Orsolya Kapuy |
| author_facet | Bence Hajdú Luca Csabai Margita Márton Marianna Holczer Tamás Korcsmáros Orsolya Kapuy |
| author_sort | Bence Hajdú |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-11T04:54:39Z |
| format | Article |
| id | doaj.art-041bcbf2a4054833a0eaca78e0e75649 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:54:39Z |
| publishDate | 2023-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-041bcbf2a4054833a0eaca78e0e756492023-11-17T19:43:55ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-04-01248767110.3390/ijms24087671Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology StudyBence Hajdú0Luca Csabai1Margita Márton2Marianna Holczer3Tamás Korcsmáros4Orsolya Kapuy5Department of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1085 Budapest, HungaryEarlham Institute, Norwich Research Park, Norwich NR4 7UG, UKDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1085 Budapest, HungaryDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1085 Budapest, HungaryEarlham Institute, Norwich Research Park, Norwich NR4 7UG, UKDepartment of Molecular Biology, Institute of Biochemistry and Molecular Biology, Semmelweis University, 1085 Budapest, HungaryOne 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.https://www.mdpi.com/1422-0067/24/8/7671feedback loopsautophagybistable switchoscillationmathematical modelling |
| spellingShingle | Bence Hajdú Luca Csabai Margita Márton Marianna Holczer Tamás Korcsmáros Orsolya Kapuy Oscillation of Autophagy Induction under Cellular Stress and What Lies behind It, a Systems Biology Study International Journal of Molecular Sciences feedback loops autophagy bistable switch oscillation mathematical modelling |
| 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 | feedback loops autophagy bistable switch oscillation mathematical modelling |
| url | https://www.mdpi.com/1422-0067/24/8/7671 |
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