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      Molecular chaperones and proteostasis regulation during redox imbalance

      , , *

      Redox Biology

      Elsevier

      α(2)M, α(2)-Macroglobulin, AGEs, Advanced Glycation End Products, ALS, Autophagy Lysosome System, AP-1, Activator Protein-1, CLU, apolipoprotein J/Clusterin, EPMs, Enzymatic Protein Modifications, ER, Endoplasmic Reticulum, ERAD, ER-Associated protein Degradation, GRP78, Glucose Regulated Protein of 78 kDa, GPx7, Glutathione Peroxidase 7, Hb, Haemoglobin, HSF1, Heat Shock transcription Factor-1, HSP, Heat Shock Protein, Keap1, Kelch-like ECH-associated protein 1, NADH, Nicotinamide Adenine Dinucleotide, NEPMs, Non-Enzymatic Protein Modifications, NOS, Nitric Oxide Synthase, NOx, NAD(P)H Oxidase, Nrf2, NF-E2-related factor 2, PDI, Protein Disulfide Isomerase, PDR, Proteome Damage Responses, PN, Proteostasis Network, RNS, Reactive Nitrogen Species, ROS, Reactive Oxygen Species, UPR, Unfolded Protein Response, UPS, Ubiquitin Proteasome System, Chaperones, Diseases, Free radicals, Oxidative stress, Proteome, Redox signalling

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          Abstract

          Free radicals originate from both exogenous environmental sources and as by-products of the respiratory chain and cellular oxygen metabolism. Sustained accumulation of free radicals, beyond a physiological level, induces oxidative stress that is harmful for the cellular homeodynamics as it promotes the oxidative damage and stochastic modification of all cellular biomolecules including proteins. In relation to proteome stability and maintenance, the increased concentration of oxidants disrupts the functionality of cellular protein machines resulting eventually in proteotoxic stress and the deregulation of the proteostasis (homeostasis of the proteome) network (PN). PN curates the proteome in the various cellular compartments and the extracellular milieu by modulating protein synthesis and protein machines assembly, protein recycling and stress responses, as well as refolding or degradation of damaged proteins. Molecular chaperones are key players of the PN since they facilitate folding of nascent polypeptides, as well as holding, folding, and/or degradation of unfolded, misfolded, or non-native proteins. Therefore, the expression and the activity of the molecular chaperones are tightly regulated at both the transcriptional and post-translational level at organismal states of increased oxidative and, consequently, proteotoxic stress, including ageing and various age-related diseases (e.g. degenerative diseases and cancer). In the current review we present a synopsis of the various classes of intra- and extracellular chaperones, the effects of oxidants on cellular homeodynamics and diseases and the redox regulation of chaperones.

          Graphical abstract

          Differential regulation of chaperones activity, under physiological conditions or during oxidative stress-mediated proteome instability.

          Highlights

          • Free radicals originate from various sources and at physiological concentrations are essential for the modulation of cell signalling pathways.

          • Abnormally high levels of free radicals induce oxidative stress and damage all cellular biomolecules, including proteins.

          • Molecular chaperones facilitate folding of nascent polypeptides, as well as holding, folding, and/or degradation of damaged proteins.

          • The expression and the activity of chaperones during oxidative stress are regulated at both the transcriptional and post-translational level.

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          Most cited references 114

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          Molecular chaperones in protein folding and proteostasis.

          Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
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            Hsp70 chaperones: Cellular functions and molecular mechanism

             M P Mayer,  B. Bukau (2005)
            Abstract. Hsp70 proteins are central components of the cellular network of molecular chaperones and folding catalysts. They assist a large variety of protein folding processes in the cell by transient association of their substrate binding domain with short hydrophobic peptide segments within their substrate proteins. The substrate binding and release cycle is driven by the switching of Hsp70 between the low-affinity ATP bound state and the high-affinity ADP bound state. Thus, ATP binding and hydrolysis are essential in vitro and in vivo for the chaperone activity of Hsp70 proteins. This ATPase cycle is controlled by co-chaperones of the family of J-domain proteins, which target Hsp70s to their substrates, and by nucleotide exchange factors, which determine the lifetime of the Hsp70-substrate complex. Additional co-chaperones fine-tune this chaperone cycle. For specific tasks the Hsp70 cycle is coupled to the action of other chaperones, such as Hsp90 and Hsp100.
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              The Nrf2 cell defence pathway: Keap1-dependent and -independent mechanisms of regulation.

              The transcription factor Nrf2 (NF-E2-related factor 2) plays a vital role in maintaining cellular homeostasis, especially upon the exposure of cells to chemical or oxidative stress, through its ability to regulate the basal and inducible expression of a multitude of antioxidant proteins, detoxification enzymes and xenobiotic transporters. In addition, Nrf2 contributes to diverse cellular functions including differentiation, proliferation, inflammation and lipid synthesis and there is an increasing association of aberrant expression and/or function of Nrf2 with pathologies including cancer, neurodegeneration and cardiovascular disease. The activity of Nrf2 is primarily regulated via its interaction with Keap1 (Kelch-like ECH-associated protein 1), which directs the transcription factor for proteasomal degradation. Although it is generally accepted that modification (e.g. chemical adduction, oxidation, nitrosylation or glutathionylation) of one or more critical cysteine residues in Keap1 represents a likely chemico-biological trigger for the activation of Nrf2, unequivocal evidence for such a phenomenon remains elusive. An increasing body of literature has revealed alternative mechanisms of Nrf2 regulation, including phosphorylation of Nrf2 by various protein kinases (PKC, PI3K/Akt, GSK-3β, JNK), interaction with other protein partners (p21, caveolin-1) and epigenetic factors (micro-RNAs -144, -28 and -200a, and promoter methylation). These and other processes are potentially important determinants of Nrf2 activity, and therefore may contribute to the maintenance of cellular homeostasis. Here, we dissect evidence supporting these Keap1-dependent and -independent mechanisms of Nrf2 regulation. Furthermore, we highlight key knowledge gaps in this important field of biology, and suggest how these may be addressed experimentally. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                30 January 2014
                30 January 2014
                2014
                : 2
                : 323-332
                Affiliations
                Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece
                Author notes
                [* ]Corresponding author. Tel.: +30 210 7274555; fax: +30 210 7274742. itrougakos@ 123456biol.uoa.gr
                Article
                S2213-2317(14)00032-9
                10.1016/j.redox.2014.01.017
                3926111
                24563850
                © 2014 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.

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