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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

ABSTRACT

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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    • "Proper unfolded protein response works as a normal cellular housekeeping process, so a complex molecular mechanism has evolved to promote proper folding, and to identify and degrade misfolded proteins. However, excessive misfolding response instigates a condition known as ER stress, which may contribute to pathological disorders such as inflammation (Hasnain et al., 2012; Hetz, 2012; Wang and Kaufman, 2012). The signaling cascades of ER stress include the 'master sensors' chaperone GRP78 (also known as BiP), as well as IRE1, PERK, and ATF6, and their downstream transcriptional effectors XBP1s, ATF4, and pATF6-N, respectively, and ultimately result in induction of genes encoding chaperones or molecules involved in ERassociated degradation (ERAD) (Hasnain et al., 2012; Janssens et al., 2014). "
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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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    • "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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