New directions in ER stress-induced cell death
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ORIGINAL PAPER
New directions in ER stress-induced cell death Susan E. Logue • Patricia Cleary • Svetlana Saveljeva Afshin Samali
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Ó Springer Science+Business Media New York 2013
Abstract Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of many diseases including heart disease, cancer and neurodegenerative diseases such as Alzheimer’s and Huntington’s. Prolonged or excessive ER stress results in the initiation of signaling pathways resulting in cell death. Over the past decade much research investigating the onset and progression of ER stress-induced cell death has been carried out. Owing to this we now have a better understanding of the signaling pathways leading to ER stress-mediated cell death and have begun to appreciate the importance of ER localized stress sensors, IRE1a, ATF6 and PERK in this process. In this article we provide an overview of the current thinking and concepts concerning the various stages of ER stressinduced cell death, focusing on the role of ER localized proteins in sensing and triggering ER stress-induced death signals with particular emphasis on the contribution of calcium signaling and Bcl-2 family members to the execution phase of this process. We also highlight new and emerging directions in ER stress-induced cell death research particularly the role of microRNAs, ER-mitochondria cross talk and the prospect of mitochondriaindependent death signals in ER stress-induced cell death. Keywords Endoplasmic reticulum Stress Unfolded protein response Cell death
S. E. Logue P. Cleary S. Saveljeva A. Samali (&) Apoptosis Research Centre, NUI Galway, Galway, Ireland e-mail: [email protected]
Introduction ER stress is triggered due to a loss of homeostasis in the ER causing accumulation of misfolded proteins within the ER lumen. Examples of such physiological stresses include hypoxia, glucose deprivation and oxidative stress, conditions which can also often be found associated with tumor microenvironments. Three ER transmembrane receptors IRE1a (inositol requiring enzyme/endonuclease 1), PERK (double stranded RNA-activated protein Kinase (PKR)-like ER kinase) and ATF6 (activating transcription factor 6) constantly monitor the ‘‘health’’ of the ER. Under normal conditions each receptor is maintained in an inactive state through binding, via their luminal domain, with the ER chaperone protein Grp78 (Bip, HspA5). Accumulation of unfolded proteins triggers dissociation of Grp78 (owing to a higher affinity for unfolded proteins) from IRE1a, PERK and ATF6 facilitating their activation. Upon Grp78 release, IRE1a dimerizes and autophosphorylates activating its kinase and endonuclease functions [1]. Likewise, PERK dimerizes and autophosphorylates, activating its kinase domain [1], while ATF6 translocates to the Golgi where site 1 protease (S1P) and site 2 protease (S2P) process it to generate an active transcription factor which subsequently translocates to the nucleus [2]. The collective signaling pathways initiated by these ER stress receptors are
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