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Int. J. Mol. Sci. 2017, 18(1), 58;

A Systems Biological View of Life-and-Death Decision with Respect to Endoplasmic Reticulum Stress—The Role of PERK Pathway

Department of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, 1094 Budapest, Hungary
Institute of Clinical Experimental Research, Semmelweis University, 1085 Budapest, Hungary
Author to whom correspondence should be addressed.
Academic Editor: Anthony Lemarié
Received: 30 September 2016 / Revised: 6 December 2016 / Accepted: 19 December 2016 / Published: 5 January 2017
(This article belongs to the Collection Programmed Cell Death and Apoptosis)
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Accumulation of misfolded/unfolded proteins in the endoplasmic reticulum (ER) leads to the activation of three branches (Protein kinase (RNA)-like endoplasmic reticulum kinase [PERK], Inositol requiring protein 1 [IRE-1] and Activating trascription factor 6 [ATF6], respectively) of unfolded protein response (UPR). The primary role of UPR is to try to drive back the system to the former or a new homeostatic state by self-eating dependent autophagy, while excessive level of ER stress results in apoptotic cell death. Our study focuses on the role of PERK- and IRE-1-induced arms of UPR in life-or-death decision. Here we confirm that silencing of PERK extends autophagy-dependent survival, whereas the IRE-1-controlled apoptosis inducer is downregulated during ER stress. We also claim that the proper order of surviving and self-killing mechanisms is controlled by a positive feedback loop between PERK and IRE-1 branches. This regulatory network makes possible a smooth, continuous activation of autophagy with respect to ER stress, while the induction of apoptosis is irreversible and switch-like. Using our knowledge of molecular biological techniques and systems biological tools we give a qualitative description about the dynamical behavior of PERK- and IRE-1-controlled life-or-death decision. Our model claims that the two arms of UPR accomplish an altered upregulation of autophagy and apoptosis inducers during ER stress. Since ER stress is tightly connected to aging and age-related degenerative disorders, studying the signaling pathways of UPR and their role in maintaining ER proteostasis have medical importance. View Full-Text
Keywords: autophagy; apoptosis; endoplasmic reticulum stress; dynamical behavior autophagy; apoptosis; endoplasmic reticulum stress; dynamical behavior

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Márton, M.; Kurucz, A.; Lizák, B.; Margittai, É.; Bánhegyi, G.; Kapuy, O. A Systems Biological View of Life-and-Death Decision with Respect to Endoplasmic Reticulum Stress—The Role of PERK Pathway. Int. J. Mol. Sci. 2017, 18, 58.

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