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

Autor: Bence Hajdú, Luca Csabai, Margita Márton, Marianna Holczer, Tamás Korcsmáros, Orsolya Kapuy
Rok vydání: 2023
Předmět:
Zdroj: International Journal of Molecular Sciences; Volume 24; Issue 8; Pages: 7671
ISSN: 1422-0067
DOI: 10.3390/ijms24087671
Popis: 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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje