title: Molecular chaperones and proteostasis regulation during redox imbalance.
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.
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Niforou
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Cheimonidou
authors.affiliation: Department of Cell Biology and Biophysics, Faculty of Biology, University of Athens, Panepistimiopolis, Athens 15784, Greece.
authors.forename: Ioannis P
authors.initials: IP
authors.lastname: Trougakos
mesh_terms: D000818:Animals; D004579:Electron Transport; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D005609:Free Radicals / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology*; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D011506:Proteins / Q000378:metabolism*; D020543:Proteome; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005609:Free Radicals; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D016877:Oxidants; D011506:Proteins; D020543:Proteome; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D046988:Proteasome Endopeptidase Complex
keywords: AGEs, Advanced Glycation End Products; ALS, Autophagy Lysosome System; AP-1, Activator Protein-1; CLU, apolipoprotein J/Clusterin; Chaperones; Diseases; EPMs, Enzymatic Protein Modifications; ER, Endoplasmic Reticulum; ERAD, ER-Associated protein Degradation; Free radicals; GPx7, Glutathione Peroxidase 7; GRP78, Glucose Regulated Protein of 78 kDa; HSF1, Heat Shock transcription Factor-1; HSP, Heat Shock Protein; Hb, Haemoglobin; 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; Oxidative stress; PDI, Protein Disulfide Isomerase; PDR, Proteome Damage Responses; PN, Proteostasis Network; Proteome; RNS, Reactive Nitrogen Species; ROS, Reactive Oxygen Species; Redox signalling; UPR, Unfolded Protein Response; UPS, Ubiquitin Proteasome System; α(2)M, α(2)-Macroglobulin