Cellular responses to endoplasmic reticulum stress and apoptosis

Abstract

The endoplasmic reticulum (ER) is the cell organelle where secretory and membrane proteins are synthesized and folded. Correctly folded proteins exit the ER and are transported to the Golgi and other destinations within the cell, but proteins that fail to fold properly-misfolded proteins-are retained in the ER and their accumulation may constitute a form of stress to the cell-ER stress. Several signaling pathways, collectively known as unfolded protein response (UPR), have evolved to detect the accumulation of misfolded proteins in the ER and activate a cellular response that attempts to maintain homeostasis and a normal flux of proteins in the ER. In certain severe situations of ER stress, however, the protective mechanisms activated by the UPR are not sufficient to restore normal ER function and cells die by apoptosis. Most research on the UPR used yeast or mammalian model systems and only recently Drosophila has emerged as a system to study the molecular and cellular mechanisms of the UPR. Here, we review recent advances in Drosophila UPR research, in the broad context of mammalian and yeast literature.

Converging Evidence of Mitochondrial Dysfunction in a Yeast Model of Homocysteine Metabolism Imbalance

“…ER stress induces adaptive cell signaling known as unfolded protein response, as a result of which ERlocalized chaperones and proteins implicated in the ER-associated degradation pathway are induced. However, if the ER stress cannot be alleviated, it culminates into apoptosis (73,74). In this study, we found that although both wild type and str4 deletion strains have similar basal unfolded protein responses in normal and under ER stress conditions, induction of unfolded protein response was not observed in the presence of AdoHcy and homocysteine in the deletion mutant, suggesting that apoptosis under these conditions might not be mediated through ER stress.…”

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

“…Under ER stress conditions, cells attempt to recover by inducing the expression of the UPR, known as the ER stress response. The UPR utilizes three types of ER-resident sensor proteins, IRE1, PERK and ATF6, that are activated by Bip (Larner et al, 2006;Lai et al, 2007;Rasheva and Domingos, 2009). The protein chaperone Bip/GRP78 is the major regulator of these pathways.…”

“…Similarly, Bip is released from IRE1 and permitted to dimerize, which activates its kinase and RNase activities to initiate XBP-1 mRNA splicing, thereby producing a potent transcriptional activator (Back et al, 2006). Finally, Bip released from ATF6 permits ATF6 transport to the Golgi compartment where it is cleaved to yield a cytosolic fragment that migrates to the nucleus to further activate the transcription of UPR-responsive genes (Haze et al, 1999;Rasheva and Domingos, 2009;Shen et al, 2004). CHOP is a non-ER-localized transcription factor that is induced by ER stress.…”

“…The ER is an organelle that is essential for cell function and survival. Interfering with ER function activates the unfolded protein response (UPR), known as the ER stress response, which is a signal to recover ER function (Ma and Hendershot, 2004;Zhang and Kaufman, 2006;Rasheva and Domingos, 2009;White-Gilbertson et al, 2013). During ER stress, multiple signaling pathways are activated, including double-stranded RNA-activated protein kinase (PKR), the PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2 alpha (eIF2α), which suppress protein synthesis (Prostko et al, 1993;Teske et al, 2011).…”

Mechanisms of exercise-induced muscle damage and fatigue: Intracellular calcium accumulation

“…The mitochondrial pathway can be initiated via intracellular damage or stress signals resulting in the release of cytochrome c from the mitochondria into the cytosol, apoptosome formation, and caspase-9 activation 47) . The endoplasmic reticulum (ER) stress pathway can be initiated by an accumulation of mis-folded and/ or unfolded proteins in the ER that can lead to ER stress, Ca 2+ release, calpain activation, and subsequent caspase-12 and caspase-9 activation 48) .…”