Role of Endoplasmic Reticulum Stress and Unfolded Protein Responses in Health and Diseases

Abstract

Endoplasmic reticulum (ER) is the site of protein synthesis, protein folding, maintainance of calcium homeostasis, synthesis of lipids and sterols. Genetic or environmental insults can alter its function generating ER stress. ER senses stress mainly by three stress sensor pathways, namely protein kinase R-like endoplasmic reticulum kinase-eukaryotic translation-initiation factor 2a, inositol-requiring enzyme 1a-X-box-binding protein 1 and activating transcription factor 6-CREBH, which induce unfolded protein responses (UPR) after the recognition of stress. Recent studies have demonstrated that ER stress and UPR signaling are involved in cancer, metabolic disorders, inflammatory diseases, osteoporosis and neurodegenerative diseases. However, the precise knowledge regarding involvement of ER stress in different disease processes is still debatable. Here we discuss the possible role of ER stress in various disorders on the basis of existing literature. An attempt has also been made to highlight the present knowledge of this field which may help to elucidate and conjure basic mechanisms and novel insights into disease processes which could assist in devising better future diagnostic and therapeutic strategies.

Protodioscin Induces Apoptosis Through ROS-Mediated Endoplasmic Reticulum Stress via the JNK/p38 Activation Pathways in Human Cervical Cancer Cells

“…Such an accumulation is referred to as the unfolded protein response (UPR); the UPR results in ER stress [8]. Recent studies have demonstrated that ER stress is involved in cancer, metabolic disorders, inflammatory diseases, and neuro-degenerative diseases [9].…”

Endoplasmic reticulum stress in chondrodysplasias caused by mutations in collagen types II and X

“…The specialized intra-ER environment contains several factors that are required for the formation of disulfide bonds and for optimal protein folding, including ATP, Ca 2+ , and unique oxidizing conditions. The accuracy of protein folding is also monitored by Ca 2+ -dependent molecular chaperones, such as glucose-regulated protein 78 kDa (Grp78/BiP), glucose-regulated protein 94 kDa (Grp94), calreticulin (CRT), and calnexin (CNX) which stabilize the protein folding intermediates and prevent the aggregation of proteins in the ER (Szegezdi et al 2006; Anelli and Sitia 2008; Kim et al 2008; Hetz 2012; Mahdi et al 2016). The physiological state of the ER is challenged when the influx of the nascent unfolded or misfolded polypeptides exceeds the processing capacity of the ER (Schröder and Kaufman 2005; Sano and Reed 2013).…”

“…If ER stress is excessive or prolonged and cannot be resolved, signaling switches from prosurvival to proapoptotic (Hosoi and Ozawa 2009; Szegezdi et al 2006). ER stress and UPR are critical for the normal cellular homeostasis and development of the organism and are also known to play major roles in the pathogenesis of many diseases such as neurodegenerative (Uehara et al 2006; Hoozemans et al 2007; Perri et al 2016) and cardiovascular (Minamino et al 2010; Kassan et al 2012) diseases, diabetes (Basha et al 2012), obesity (Hosoi et al 2008), inflammation (Ha et al 2015), and cancer (Suh et al 2012; Chhabra et al 2015; Lin et al 2008; Mahdi et al 2016; Yoshida 2007a). In recent years, accumulating evidence indicates that abnormal folding and accumulation of structural proteins that are produced to fulfil their physiological function in the extracellular space of tissues may lead to ER stress and induction of a wide range of systemic diseases.…”

Endoplasmic Reticulum Stress Is Involved in Cochlear Cell Apoptosis in a Cisplatin-Induced Ototoxicity Rat Model

“…Nevertheless, severe or persistent ER stress, which overloads the buffering capacity of the UPR, leads to apoptosis. ER stress-mediated apoptosis has been recently proved to be associated with metabolic disorders, neurodegenerative diseases, inflammatory diseases, and numerous other pathologic processes [Mahdi et al, 2016], including several types of deafness, such as hereditary [Hu et al, 2016a], age-related [Wang et al, 2015], and aminoglycoside-induced [Oishi et al, 2015] hearing loss.…”