Specifically, ROS have been shown to regulate a wide variety of signalling pathways including anti- inflammatory responses and adaptation to hypoxia [77,78], autop- hagy [79], immune cell function [80], cellular differentiation [81], integrins [82], as well as oncogenes signalling [83].
Free radicals were originally believed to be harmful, but it has been realized that in physiological concentrations they serve as redox messengers, which are essential in the regulation of intra- cellular signalling and significant cellular processes including meta- bolism, antioxidant defenses and responses to pathogens [1,4].
Free radicals-derived protein modification can result in either gain- or loss-of-function due to the protein misfolding or unfolding.
Proteome oxidation and instability has been associated with ageing and the progression of several age-related diseases, including cardiovascular disorders, neu- rodegeneration, and cancer [7,95,96].
A frequent oxidative modification of proteins is irreversible carbonylation which can occur by either direct oxidation where oxidants act and leave a functional carbonyl group on amino acid side chains or in the protein backbone, or, indirectly, by protein conjugation with oxidation pro- ducts of polyunsaturated fatty acids and carbohydrates [98].
Notably, free radicals may also arise from exogenous sources including various types of radiations (e.g. UV light, X-rays or gamma rays), atmospheric pollutants and metal-catalyzed reac- tions [1–3].
HSF1 binds to a consensus heat shock element (HSE) within the promoter regions of HSP genes resulting in the activation of HSPs' gene expression and the control of cellular responses to oxidative and proteotoxic stress [108].
Excessive amounts of free radicals and radical-derived reactive species may also arise from the activity of NAD(P)H oxidases (NOx) and/or xanthine oxidase, as well as from nitric oxide synthase (NOS), P450 metabolism and peroxisomes.
Moreover, it was shown that the concentration of the extracellular heat shock protein 72 (eHSP72) increases during exercise-heat stress [65].
Moreover, HSP22 stimu- lates autophagy-mediated degradation of protein aggregates in an eIF2α-dependent manner [30].
Excessive amounts of ROS may also arise from inflammatory processes [75].
sHSPs are tightly regulated by EPMs (e.g. phosphorylation) that enable them to respond upon stress and to perform their chaperone activities [25,26].
Upon ER proteotoxic stress, GRP78 dissociates from its binding partners, which are then free to trigger the Unfolded Protein Response (UPR) by regulating specific gene responses aiming to restore ER proteome stability.
The three sensors of ER proteotoxic stress facilitate contra- dictory responses since they either promote cell survival by decreasing the misfolded protein and/or oxidative load, or, if UPR fails, they promote the activation of apoptotic pathways that eventually result in cell death [57].
Oxidative stress abrogates the Keap1-mediated degradation of Nrf2 which in turn accumulates in the nucleus where it heterodimerizes with a small musculoapo- neurotic fibrosarcoma (Maf) protein on antioxidant response elements (AREs) to stimulate the expression of a wide arrays of phase II and antioxidant enzymes including NAD(P)H quinone oxidoreductase 1 (Nqo1), heme oxygenase 1 (Hmox1), glutamane- cysteine ligase (GCL) and glutathione S transferases (GSTs) [84,85,87,88].
Additional studies in mammalian peroxiredoxins showed that over-oxidation induces the formation of high molecular weight oligomers which function as potent chaperones and prevent protein aggregation [128,129];
sHSPs are overexpressed upon many different types of stress as they are key components of the PN and PDR.
During elevated stress the chaperones within the repressive HSF1-containing multi-chaperone complexes bind the unfolded proteins and thus the liberated monomeric HSF1s undergo phosphorylation, trimerization and nuclear localization with increased transcriptional activity [109].
Proteome is modified post-translationally by either numerous highly regulated enzymatic protein modifications (EPMs) (e.g. phosphorylation, acetylation, ubiquitination, methylation, etc.) or by non-enzymatic protein modifications (NEPMs), which are mostly stochastic and increase with ageing or in age-related diseases (Fig. 1).
EPMs alter the targeted proteins, which however remain fully functional, while NEPMs may induce protein unfolding or misfolding resulting in increased proteome instability.
In those organismal states (e.g. ageing or diseases) where the chaperone network becomes deregulated, the accumulating non-native, misfolded or unfolded proteins can form (among others) fibrils, amyloids or large amorphous aggregates [15].
Heavily carbonylated proteins tend to form aggregates that are resistant to degradation and accumulate as unfolded or damaged proteins [101].
Moreover, Nrf2 contributes to cellular proteostasis by regulating the expression of molecular chaperones [89], as well as of additional players of proteome stability and maintenance, namely the proteasome subunits [90–92].
n general, HSP90s are more specialized than other chaperones and are essential for survival in eukaryotic cells as they also are capable of binding non-native polypeptides (at the late stages of their folding) and preventing their aggregation [14].
HSP70 chaperones have a diverse array of cellular functions but their major role is to ensure correct folding of newly synthesized proteins and to perform the refolding of proteins that are misfolded and/or aggregated.
Primary cellular defensive mechanisms include enzymes like the superoxide dismutases, SOD1 (Cu–Zn SOD) and SOD2 (MnSOD) that convert superoxide to H 2 O 2 and catalase or glutathione peroxidase that convert H 2 O 2 to H 2 O;
PDI is a redox sensitive chaperone that acts not only as a sensor but also as a protein involved in the processing of oxidized proteins and in preventing misfolding and/or aggregation of proteins.
These chaperones provide high-affinity binding platforms for unfolded proteins and prevent protein aggregation specifically during stress conditions.
Specifically, they have been found overexpressed in many different diseases including various types of cancer where they contribute in reducing proteotoxic stress [7].
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If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.