PubMed: 24563850

Molecular chaperones and proteostasis regulation during redox imbalance.
Redox biology
Cheimonidou C | Niforou K | Trougakos IP

Evidence 008ada1417

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].

Evidence f87d6ebf01

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].

Evidence 8bd49fbe95

Free radicals-derived protein modification can result in either gain- or loss-of-function due to the protein misfolding or unfolding.

Evidence cdc54d7930

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].

Evidence f535045431

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].

Evidence 826fd31f84

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].

Evidence bf174f3ea2

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].

Evidence 49a7db8a80

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.

Evidence 6c2a6e47cd

Moreover, it was shown that the concentration of the extracellular heat shock protein 72 (eHSP72) increases during exercise-heat stress [65].

Evidence 8aa1e86fb9

Moreover, HSP22 stimu- lates autophagy-mediated degradation of protein aggregates in an eIF2α-dependent manner [30].

Evidence b9624ffa04

Excessive amounts of ROS may also arise from inflammatory processes [75].

Evidence a37ad28518

sHSPs are tightly regulated by EPMs (e.g. phosphorylation) that enable them to respond upon stress and to perform their chaperone activities [25,26].

Evidence f8c383a392

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.

Evidence c0f58f948a

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].

Evidence 6ad0cd6ab2

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].

Evidence f94104694c

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];

Evidence 97ac348a42

sHSPs are overexpressed upon many different types of stress as they are key components of the PN and PDR.

Evidence faedae9937

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].

Evidence d6af580ffb

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).

Evidence f6e7a277a2

EPMs alter the targeted proteins, which however remain fully functional, while NEPMs may induce protein unfolding or misfolding resulting in increased proteome instability.

Evidence d4215c4d71

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].

Evidence eedb1f423a

Heavily carbonylated proteins tend to form aggregates that are resistant to degradation and accumulate as unfolded or damaged proteins [101].

Evidence 8f5232f379

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].

Evidence baa8870624

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].

Evidence 5698fd75ca

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.

Evidence c78eab3c07

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;

Evidence df83d57569

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.

Evidence 44794f16bb

These chaperones provide high-affinity binding platforms for unfolded proteins and prevent protein aggregation specifically during stress conditions.

Evidence a069273225

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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