Wang S, Kaufman RJThe impact of the unfolded protein response on human disease. J Cell Biol 197:857-867

Degenerative Disease Research Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 06/2012; 197(7):857-67. DOI: 10.1083/jcb.201110131
Source: PubMed


A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

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    • "Perturbations in ER homeostasis, such as elevated rates of secretory or membrane protein biosynthesis, elevated rates of lipid biosynthesis, and decreased calcium concentration, can disrupt protein modification and folding, resulting in the accumulation of unfolded or misfolded proteins in the ER lumen. This build up of unfolded or misfolded proteins is known as ER stress and results in the activation of the unfolded protein response (UPR, Figure 1) (Marciniak and Ron, 2006; Walter and Ron, 2011; Wang and Kaufman, 2012). Three ER-transmembrane proteins have been identified as the transducers of the UPR, pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). "
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    ABSTRACT: The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is comprised of three signaling pathways that promote cytoprotective functions to correct ER stress; however, if ER stress cannot be resolved the UPR results in apoptosis of affected cells. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS. In this review we will cover current literature on the UPR and the evidence for its role in the development of MS.
    Frontiers in Neuroscience 08/2015; 9:264. DOI:10.3389/fnins.2015.00264 · 3.66 Impact Factor
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    • "Third, Inositol-requiring enzyme 1 (IRE1) cuts the precursor XBP1 mRNA twice, removing an internal fragment and thus inducing a frame shift. ER stress responses provide a conserved mechanism by reducing the folded protein load (eIF2í µí»¼ phosphorylation and ERAD degradation) and increase the folding capacity (induction of Bip/GRP78) [9] [10]. It has been shown that acrolein induces these three UPRs [11] [12] [13] [14]. "
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    ABSTRACT: Chronic obstructive pulmonary disease (COPD) is characterized by lung destruction and inflammation. As a major compound of cigarette smoke, acrolein plays a critical role in the induction of respiratory diseases. GADD34 is known as a growth arrest and DNA damage-related gene, which can be overexpressed in adverse environmental conditions. Here we investigated the effects of GADD34 on acrolein-induced lung injury. The intranasal exposure of acrolein induced the expression of GADD34, developing the pulmonary damage with inflammation and increase of reactive oxygen species (ROS). Conversely, the integrality of pulmonary structure was preserved and the generation of ROS was reduced in GADD34-knockout mice. Acrolein-induced phosphorylation of eIF2α in GADD34-knockout epithelial cells by shRNA protected cell death by reducing misfolded protein-caused oxidative stress. These data indicate that GADD34 participates in the development of acrolein-induced lung injury.
    Oxidative Medicine and Cellular Longevity 03/2015; 2015:170309. DOI:10.1155/2015/170309 · 3.36 Impact Factor
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    • "Tel: +81–791–58–0212, Fax: +81–791–58–0219 E-mail: Web site: **Correspondence: Hiroshi Kitagawa, the ER stress response (also called the unfolded protein response) and increase the protein-folding capacity of the ER (Kimata and Kohno, 2011; Mori, 2009; Ron and Harding, 2012; Walter and Ron, 2011; Wang and Kaufman, 2012; Yoshida, 2009). The mammalian ER stress response consists of three main mechanisms: the ATF6, IRE1 and PERK pathways. "
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    ABSTRACT: The Golgi stress response is a mechanism by which, under conditions of insufficient Golgi function (Golgi stress), the transcription of Golgi-related genes is upregulated through an enhancer, the Golgi apparatus stress response element (GASE), in order to maintain homeostasis in the Golgi. The molecular mechanisms associated with GASE remain to be clarified. Here, we identified TFE3 as a GASE-binding transcription factor. TFE3 was phosphorylated and retained in the cytoplasm in normal growth conditions, whereas it was dephosphorylated, translocated to the nucleus and activated Golgi-related genes through GASE under conditions of Golgi stress, e.g. in response to inhibition of oligosaccharide processing in the Golgi apparatus. From these observations, we concluded that the TFE3-GASE pathway is one of the regulatory pathways of the mammalian Golgi stress response, which regulates the expression of glycosylation-related proteins in response to insufficiency of glycosylation in the Golgi apparatus.
    Cell Structure and Function 11/2014; 40(1). DOI:10.1247/csf.14015 · 1.68 Impact Factor
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