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

Abstract

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.

The Dual Role of Sulforaphane-Induced Cellular Stress—A Systems Biological Study

“…Cellular life-and-death decision is one of the most important tasks of a living organism to answer the drastic effects of various external and internal stimuli (such as endoplasmic reticulum stress, starvation, etc.). Recently, we have developed a simple mathematical model that was able to describe the important regulatory connections of the control network, claiming the importance of the double-negative feedback loops between the surviving and cell-death mechanisms [ 23 , 25 ]. We supposed that these feedback loops guaranteed the switch-like characteristic of the response corresponding to the level of cellular stress [ 23 , 25 ].…”

“…Recently, we have developed a simple mathematical model that was able to describe the important regulatory connections of the control network, claiming the importance of the double-negative feedback loops between the surviving and cell-death mechanisms [ 23 , 25 ]. We supposed that these feedback loops guaranteed the switch-like characteristic of the response corresponding to the level of cellular stress [ 23 , 25 ]. In the last couple of years, we also confirmed the important roles of various natural compounds (i.e., resveratrol, EGCG) in extending autophagy-dependent cell survival by postponing ER stress-induced apoptotic cell death.…”

“…Previously, our group has made some mathematical models to analyze the ER stress-response mechanism [ 17 , 18 ], focusing on the crosstalk between autophagy and apoptosis [ 19 , 20 ] and the autophagy-dependent survival mechanism under various types of cellular stress [ 21 , 22 , 23 , 24 ]. We have found that autophagy can be periodically activated due to the delayed negative feedback loop between AMPK and ULK1 [ 22 , 25 ]. Furthermore, we have claimed that a robust autophagy response mechanism requires double-negative and positive feedback loops in the system [ 24 ].…”

Mechanism of Decision Making between Autophagy and Apoptosis Induction upon Endoplasmic Reticulum Stress

“…Since hyperactivation of the ER stress response can also be dangerous for the cell (e.g., uncontrolled autophagy can cause cell death [153]), negative feedback loops in the system via eiF2a -> GADD34 −| eiF2α and ATF4 -> CHOP −| ATF4 are very important to prevent over-expression of the UPR members by the target proteins blocking their own activators [127]. Some experimental data have revealed that the negative feedback loop can cause the oscillatory characteristic of autophagy induction upon various stress events (such as rapamycin treatment or food deprivation), thus ensuring that the system can re-use the components generated by self-digestion, but not upon ER stress [154,155]. In a recent theoretical analysis, Erguler et al explore the dynamical characteristic of the ER stress response mechanism at various levels of stress, and they claim that the intermediate state of UPR, due to moderate level of ER stress, might generate sustained oscillation of the key components of the network [156].…”