Article

The Endoplasmic Reticulum and the Unfolded Protein Response

Howard Hughes Medical Institute, Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, United States.
Seminars in Cell and Developmental Biology (Impact Factor: 6.27). 01/2008; 18(6):716-31. DOI: 10.1016/j.semcdb.2007.09.003
Source: PubMed

ABSTRACT

The endoplasmic reticulum (ER) is the site where proteins enter the secretory pathway. Proteins are translocated into the ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to attain their final appropriate conformation. A sensitive surveillance mechanism exists to prevent misfolded proteins from transiting the secretory pathway and ensures that persistently misfolded proteins are directed towards a degradative pathway. In addition, those processes that prevent accumulation of unfolded proteins in the ER lumen are highly regulated by an intracellular signaling pathway known as the unfolded protein response (UPR). The UPR provides a mechanism by which cells can rapidly adapt to alterations in client protein-folding load in the ER lumen by expanding the capacity for protein folding. In addition, a variety of insults that disrupt protein folding in the ER lumen also activate the UPR. These include changes in intralumenal calcium, altered glycosylation, nutrient deprivation, pathogen infection, expression of folding-defective proteins, and changes in redox status. Persistent protein misfolding initiates apoptotic cascades that are now known to play fundamental roles in the pathogenesis of multiple human diseases including diabetes, atherosclerosis and neurodegenerative diseases.

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    • "The absence of one or both of the Arabidopsis calnexins in general led to elevation of transcript of other ER chaperones, some of which are involved in the unfolded protein response and ER stress. Over-accumulation of proteins in the ER beyond the folding capacity of existing chaperones can lead to UPR induction, which is, in turn, known to up-regulate expression of ER chaperones (Malhotra and Kaufman 2007; Liu and Howell 2010). While within the calnexin family there was some transcript-level compensation for CNX1 deficiency by CNX2, compensation for the absence of CNX1 or CNX2 transcript extended to other chaperones. "
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    ABSTRACT: We examined the physiological significance of the nuclear versus cytosolic localization of the MAPK Hog1p in the ability of yeast cells to cope with osmotic and ER stress. Our results indicate that nuclear import of Hog1p is not critical for osmoadaptation. Plasma membrane-anchored Hog1p is still able to induce increased expression of GPD1 and glycerol accumulation. This is a key osmoregulatory event, although a small production of the osmolyte coupled with the nuclear import of Hog1p is sufficient to provide osmoresistance. On the contrary, the nuclear activity of Hog1p is dispensable for ER stress adaptation. Copyright © 2015. Published by Elsevier B.V.
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    • "Overproduction of recombinant proteins may overload the ER folding and secretion capacity, resulting in the accumulation of misfolded or unfolded proteins, and ER stress as a consequence . This triggers the activation of the unfolded protein response (UPR) pathway, which aims at reducing ER stress conditions by induction of genes involved in protein folding and the ER-associated degradation (ERAD) pathway (Hoseki et al. 2010; Kohno 2010; Malhotra and Kaufman 2007; Vembar and Brodsky 2008). We have shown that these effects also occur in P. pastoris upon heterologous protein production (Hohenblum et al. 2004). "
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