Molecular chaperones and proteostasis regulation during redox imbalance

• 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.

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.

Differential regulation of chaperones activity, under physiological conditions or during oxidative stress-mediated proteome instability.Figure optionsDownload as PowerPoint slide