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


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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    • "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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    ABSTRACT: The development of Pichia pastoris as a production platform for recombinant proteins has been a remarkable success story over the last three decades. Stable cheap production processes and the good protein secretion abilities were pacemakers of this development. However, limitations of protein folding, glycosylation or secretion have been identified quite early on. With the availability of genome sequences and the development of systems biology characterization in the last 5 years, remarkable success in strain improvement was achieved. Here, we focus on recent developments of characterization and improvement of P. pastoris production strains regarding protein folding, intracellular trafficking, glycosylation and proteolytic degradation.
    Applied Microbiology and Biotechnology 02/2015; 99(7). DOI:10.1007/s00253-015-6470-z · 3.34 Impact Factor
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    • "The endoribonuclease domain of IRE1α is responsible for XBP-1 mRNA splicing [74] [75]. Active XBP-1 enters the nucleus and binds to the promoter region of the ER stress-response element (ERSE), which induces the transcription of ERAD-and chaperone-related genes [4] [76]. XBP-1 is also responsible for the expression of P58 IPK , which negatively regulates PERK activity [77], and phospholipid synthesis for ER membrane expansion, which is a specific response to ER stress [6]. "
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    ABSTRACT: The folding process is an important step in protein synthesis for the functional shape or conformation of the protein. The endoplasmic reticulum (ER) is the main organelle for the correct folding procedure, which maintains the homeostasis of the organism. This process is normally well organized under unstressed conditions, whereas it may fail under oxidative and ER stress. The unfolded protein response (UPR) is a defense mechanism that removes the unfolded/misfolded proteins to prevent their accumulation, and two main degradation systems are involved in this defense, including the proteasome and autophagy. Cells decide which mechanism to use according to the type, severity, and duration of the stress. If the stress is too severe and in excess, the capacity of these degradation mechanisms, proteasomal degradation and autophagy, is not sufficient and the cell switches to apoptotic death. Because the accumulation of the improperly folded proteins leads to several diseases, it is important for the body to maintain this balance. Cardiovascular diseases are one of the important disorders related to failure of the UPR. Especially, protection mechanisms and the transition to apoptotic pathways have crucial roles in cardiac failure and should be highlighted in detailed studies to understand the mechanisms involved. This review is focused on the involvement of the proteasome, autophagy, and apoptosis in the UPR and the roles of these pathways in cardiovascular diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
    Free Radical Biology and Medicine 10/2014; 78. DOI:10.1016/j.freeradbiomed.2014.09.031 · 5.74 Impact Factor
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    • "Actually, an IRE1-independent surveillance mechanism that monitors protein folding in the ER has been indicated in yeast [35] and in metazoan cells. There are already three mechanistically distinct pathways, mediated by IRE1, ATF6 and PERK respectively, known to operate in parallel to activate UPR in mammalians [36]. A study overexpressing membrane protein in A. niger showed the mRNA level of BipA (encoded by KAR2) was elevated while no truncated hacA transcript was detected [37]. "
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    ABSTRACT: Background The koji mold, Aspergillus oryzae is widely used for the production of industrial enzymes due to its particularly high protein secretion capacity and ability to perform post-translational modifications. However, systemic analysis of its secretion system is lacking, generally due to the poorly annotated proteome. Results Here we defined a functional protein secretory component list of A. oryzae using a previously reported secretory model of S. cerevisiae as scaffold. Additional secretory components were obtained by blast search with the functional components reported in other closely related fungal species such as Aspergillus nidulans and Aspergillus niger. To evaluate the defined component list, we performed transcriptome analysis on three α-amylase over-producing strains with varying levels of secretion capacities. Specifically, secretory components involved in the ER-associated processes (including components involved in the regulation of transport between ER and Golgi) were significantly up-regulated, with many of them never been identified for A. oryzae before. Furthermore, we defined a complete list of the putative A. oryzae secretome and monitored how it was affected by overproducing amylase. Conclusion In combination with the transcriptome data, the most complete secretory component list and the putative secretome, we improved the systemic understanding of the secretory machinery of A. oryzae in response to high levels of protein secretion. The roles of many newly predicted secretory components were experimentally validated and the enriched component list provides a better platform for driving more mechanistic studies of the protein secretory pathway in this industrially important fungus.
    BMC Systems Biology 06/2014; 8(1):73. DOI:10.1186/1752-0509-8-73 · 2.44 Impact Factor
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