Cell death induced by endoplasmic reticulum stress

Abstract

The endoplasmic reticulum (ER) is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occur in this organelle. Many Author ManuscriptThis article is protected by copyright. All rights reserved conditions that impose stress to the cells, including hypoxia, starvation, infections and changes in secretory needs challenge the folding capacity of the cell and promote ER stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim to restore homeostasis. This is known as the Unfolded Protein Response (UPR), which also intersects with the Integrated Stress Response (ISR) that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the UPR are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as JNK and the downstream transcription factors XBP-1, ATF4 and CHOP. These proteins aim to restore homeostasis but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. Additionally, ER stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of Caspase-8.ER stress is a common feature in the pathology of numerous diseases as it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to ER stress can accelerate discovery of drugs against these diseases. KeywordsEndoplasmic reticulum stress The endoplasmic reticulum and the Unfolded Protein Response sensorsThe endoplasmic reticulum (ER) is the organelle where transmembrane proteins and proteins that are going to be secreted are synthesized and folded. This organelle, however, is essential for multiple other cellular functions such as Ca 2+ buffering, biosynthesis of phospholipids and cholesterol. Synthesis of proteins, cholesterol and some metabolites is an ATP demanding process that also requires the right ionic strength. Disturbances in many homeostatic processes will thus lead to a state in which protein folding slows down (ER stress). The subsequent accumulation of misfolded or unfolded proteins will indicate problems in cellular homeostasis that frequently end up in cell death.Problems in protein folding can occur due to stressors apparently disparate such as starvation or viral infection. These stimuli promote the activation of a series of signals that promote synthesis of new proteins to cope with stress while reducing general protein synthesis [1,2]. This is called the Unfolded Protein Response (UPR). Another way by which the UPR aims to restore homeostasis is the stimulation of protein degradation via autophagy and the enhanced clearance of unfolded proteins by a process termed ER-Associated Degradation (ERAD).The UPR is orchestrated by three main sensors that reside in the membrane of the ER. These transmembrane proteins bind to the chaperone GRP78/BiP in the...

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