Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events

Kapuy, Orsolya; Holczer, Marianna; Márton, Margita; Korcsmáros, Tamás

doi:10.1038/s41419-021-03599-7

Cited by 15 publications

(21 citation statements)

References 74 publications

(56 reference statements)

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“…Similar regulatory connection was characterized with Dr. Tamás Korcsmáros, when we proved that NRF2 had a negative feedback on its activator, called AMPK [ 60 , 61 ]. Our analysis has indicated that this negative feedback loop has an essential role in preventing the hyperactivation of autophagy induced by both AMPK and NRF2 [ 62 ]. Similar to this observation, here we also suggest that CHOP blocks the hyperactivation of ATF4 upon an excessive level of ER stress.…”

Section: Discussionmentioning

confidence: 99%

A systems biological analysis of the ATF4‐GADD34‐CHOP regulatory triangle upon endoplasmic reticulum stress

et al. 2022

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Endoplasmic reticulum (ER) stress‐dependent accumulation of incorrectly folded proteins leads to activation of the unfolded protein response. The role of the unfolded protein response (UPR) is to avoid cell damage and restore the homeostatic state by autophagy; however, excessive ER stress results in apoptosis. Here we investigated the ER stress‐dependent feedback loops inside one of the UPR branches by focusing on PERK‐induced ATF4 and its two targets, called CHOP and GADD34. Our goal was to qualitatively describe the dynamic behavior of the system by exploring the key regulatory motifs using both molecular and theoretical biological techniques. Using the HEK293T cell line as a model system, we confirmed that the life‐or‐death decision is strictly regulated. We investigated the dynamic characteristics of the crucial elements of the PERK pathway at both the RNA and protein level upon tolerable and excessive levels of ER stress. Of particular note, inhibition of GADD34 or CHOP resulted in various phenotypes upon high levels of ER stress. Our computer simulations suggest the existence of two new feedback loops inside the UPR. First, GADD34 seems to have a positive effect on ATF4 activity, while CHOP inhibits it. We claim that these newly described feedback loops ensure the fine‐tuning of the ATF4‐dependent stress response mechanism of the cell.

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Section: Discussionmentioning

confidence: 99%

A systems biological analysis of the ATF4‐GADD34‐CHOP regulatory triangle upon endoplasmic reticulum stress

et al. 2022

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“…This indicates that the DNA damage generated by the compounds is so intense that the autophagy process cannot protect the cell. Recently, there has been an intensified discussion on the phenomenon of “autophagy switch” [ 36 ].…”

Section: Resultsmentioning

confidence: 99%

Hexokinase 2 Inhibition and Biological Effects of BNBZ and Its Derivatives: The Influence of the Number and Arrangement of Hydroxyl Groups

Juszczak

Kubicka

Kitel

et al. 2022

IJMS

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Hexokinase 2 (HK2), an enzyme of the sugar kinase family, plays a dual role in glucose metabolism and mediating cancer cell apoptosis, making it an attractive target for cancer therapy. While positive HK2 expression usually promotes cancer cells survival, silencing or inhibiting this enzyme has been found to improve the effectiveness of anti-cancer drugs and even result in cancer cell death. Previously, benitrobenrazide (BNBZ) was characterized as a potent HK2 inhibitor with good anti-cancer activity in mice, but the effect of its trihydroxy moiety (pyrogallol-like) on inhibitory activity and some cellular functions has not been fully understood. Therefore, the main goal of this study was to obtain the parent BNBZ (2a) and its three dihydroxy derivatives 2b–2d and to conduct additional physicochemical and biological investigations. The research hypothesis assumed that the HK2 inhibitory activity of the tested compounds depends on the number and location of hydroxyl groups in their chemical structure. Among many studies, the binding affinity to HK2 was determined and two human liver cancer cell lines, HepG2 and HUH7, were used and exposed to chemicals at various times: 24 h, 48 h and 72 h. The study showed that the modifications to the structures of the new BNBZ derivatives led to significant changes in their activities. It was also found that these compounds tend to aggregate and exhibit toxic effects. They were found to contribute to: (a) DNA damage, (b) increased ROS production, and (c) disruption of cell cycle progression. It was observed that, HepG2, occurred much more sensitive to the tested chemicals than the HUH7 cells; However, regardless of the used cell line it seems that the increase in the expression of HK2 in cancer cells compared to normal cells which have HK2 at a very low level, is a serious obstacle in anti-cancer therapy and efforts to find the effective inhibitors of this enzyme should be intensified.

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“…The proper response of cells to both the anabolic metabolites around them and to adverse cellular stresses (such as oxidative stress or starvation) is essential for survival. By using systems biological techniques, recently we have shown the dynamical features of mTORC1-AMPK-ULK1 regulatory triangle induced autophagy-dependent survival upon various cellular stress events [ 10 , 38 , 39 ]. We claim that the feedback loops between these three kinases are essential for the proper induction of autophagy, where rapid phosphorylation steps are able to generate a rapid response.…”

Section: Discussionmentioning

confidence: 99%

Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress

et al. 2022

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Autophagy-dependent cellular survival is tightly regulated by both kinases and phosphatases. While mTORC1 inhibits autophagy by phosphorylating ULK1, PP2A is able to remove this phosphate group from ULK1 and promotes the key inducer of autophagosome formation. However, ULK1 inhibits mTORC1, mTORC1 is able to down-regulate PP2A. In addition, the active ULK1 promotes PP2A via phosphorylation. We claim that these double-negative (mTORC1 –| PP2A –| mTORC1, mTORC1 –| ULK1 –| mTORC1) and positive (ULK1 -> PP2A -> ULK1) feedback loops are all necessary for the robust, irreversible decision making process between the autophagy and non-autophagy states. We approach our scientific analysis from a systems biological perspective by applying both theoretical and molecular biological techniques. For molecular biological experiments, HEK293T cell line is used, meanwhile the dynamical features of the regulatory network are described by mathematical modelling. In our study, we explore the dynamical characteristic of mTORC1-ULK1-PP2A regulatory triangle in detail supposing that the positive feedback loops are essential to manage a robust cellular answer upon various cellular stress events (such as mTORC1 inhibition, starvation, PP2A inhibition or ULK1 silencing). We confirm that active ULK1 can up-regulate PP2A when mTORC1 is inactivated. By using theoretical analysis, we explain the importance of cellular PP2A level in stress response mechanism. We proved both experimentally and theoretically that PP2A down-regulation (via addition of okadaic acid) might generate a periodic repeat of autophagy induction. Understanding how the regulation of the cell survival occurs with the precise molecular balance of ULK1-mTORC1-PP2A in autophagy, is highly relevant in several cellular stress-related diseases (such as neurodegenerative diseases or diabetes) and might help to promote advanced therapies in the near future, too.

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Autophagy-dependent survival is controlled with a unique regulatory network upon various cellular stress events

Cited by 15 publications

References 74 publications

A systems biological analysis of the ATF4‐GADD34‐CHOP regulatory triangle upon endoplasmic reticulum stress

A systems biological analysis of the ATF4‐GADD34‐CHOP regulatory triangle upon endoplasmic reticulum stress

Hexokinase 2 Inhibition and Biological Effects of BNBZ and Its Derivatives: The Influence of the Number and Arrangement of Hydroxyl Groups

Fine-Tuning of mTORC1-ULK1-PP2A Regulatory Triangle Is Crucial for Robust Autophagic Response upon Cellular Stress

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