Redox sensing: orthogonal control in cell cycle and apoptosis signalling.

Abstract

Living systems have three major types of cell signalling systems that are dependent upon high-energy chemicals, redox environment and transmembranal ion-gating mechanisms. Development of integrated systems biology descriptions of cell signalling require conceptual models incorporating all three. Recent advances in redox biology show that thiol-disulphide redox systems are regulated under dynamic, nonequilibrium conditions, progressively oxidized with the life cycle of cells and distinct in terms of redox potentials amongst subcellular compartments. This article uses these observations as a basis to distinguish 'redox-sensing' mechanisms, which are more global biologic redox control mechanisms, from 'redox signalling', which involves conveyance of discrete activating or inactivating signals. Both redox sensing and redox signalling use sulphur switches, especially cysteine (Cys) residues in proteins which are sensitive to reversible oxidation, nitrosylation, glutathionylation, acylation, sulfhydration or metal binding. Unlike specific signalling mechanisms, the redox-sensing mechanisms provide means to globally affect the rates and activities of the high-energy, ion-gating and redox-signalling systems by controlling sensitivity, distribution, macromolecular interactions and mobility of signalling proteins. Effects mediated through Cys residues not directly involved in signalling means redox-sensing control can be orthogonal to the signalling mechanisms. This provides a capability to integrate signals according to cell cycle and physiologic state without fundamentally altering the signalling mechanisms. Recent findings that thiol-disulphide pools in humans are oxidized with age, environmental exposures and disease risk suggest that redox-sensing thiols could provide a central mechanistic link in disease development and progression.