Department of Medicine, Emory University, Atlanta, GA 30322, USA.
J Intern Med. 2010 Nov;268(5):432-48. doi: 10.1111/j.1365-2796.2010.02268.x.
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.
生命系统有三种主要的细胞信号系统，它们依赖于高能化学物质、氧化还原环境和跨膜离子门控机制。综合系统生物学描述细胞信号的发展需要包含所有这三种的概念模型。氧化还原生物学的最新进展表明，硫醇-二硫键氧化还原系统在动态、非平衡条件下受到调节，随着细胞生命周期逐渐被氧化，并且在亚细胞区室之间的氧化还原电位方面是不同的。本文利用这些观察结果，将“氧化还原感应”机制与“氧化还原信号”区分开来，后者涉及离散的激活或失活信号的传递。氧化还原感应和氧化还原信号都使用硫开关，特别是蛋白质中的半胱氨酸（Cys）残基，它们对可逆氧化、亚硝基化、谷胱甘肽化、酰化、硫代或金属结合敏感。与特定的信号机制不同，氧化还原感应机制通过控制信号蛋白的敏感性、分布、大分子相互作用和流动性，提供了一种全局影响高能、离子门控和氧化还原信号系统的速率和活性的手段。不直接参与信号的 Cys 残基介导的效应意味着氧化还原感应控制可以与信号机制正交。这提供了根据细胞周期和生理状态整合信号的能力，而无需从根本上改变信号机制。最近的发现表明，人类的硫醇-二硫键库随着年龄、环境暴露和疾病风险而氧化，这表明氧化还原感应硫醇可以为疾病的发展和进展提供一个核心的机制联系。
