The Expanding List of Redox-Sensing Transcription Factors in Mammalian Cells

Mammalian cells do not survive in the absence of redox reactions; oxidation and reduction predominate in the swamp of metabolic biochemical reactions inside the cell. In a situation which is less stoichiometric, subtle alterations of the redox status in the intracellular environment also have significant impacts on cell biology. Changes in the intracellular redox status can be assessed by quantifying the reduction potentials of various intracellular redox couples [1]. However, in practice, the motto “redox environment” used by cell biologists usually means the relative abundance of reactive oxygen species (ROS) inside or in proximity of a cell. More than three decades ago people have observed that mammalian cells can actively produce ROS, and utilize these molecules to regulate cell functions [2]. Then it has been discovered that in prokaryotes, some transcription factors switch on and off their DNA binding activity by directly sensing the presence of pro oxidant ROS molecules such as superoxide and hydrogen peroxide, which regulate gene expressions [3]. This phenomenon was also observed in mammalian cells [4]. The term “redox signaling” was coined to describe the process that cells use ROS (including nitric oxide) molecules to carry out intracellular or intercellular communications [5]. The principal molecular mechanism of the redox sensing property of proteins relies on redox modifications of thiol moieties (generally those associated with key cysteine residues) by ROS (oxidation) or nitric oxide (S-nitrosylation) [6]. When discussing redox regulation, we should distinguish whether the relevant signaling proteins are direct redox sensors (i.e., their functions are modulated by redox modification of the proteins per se), or alternatively the activity of the signaling protein is indirectly affected by ROS via other redox sensors. The second issue that needs to be considered is whether the target protein is responsive to intracellularly produced ROS molecules (e.g., from NADPH oxidase or mitochondria, which may be regarded as genuine cellular signal messengers), or can only be activated or inhibited by exogenously applied ROS (mimicking a situation of severe oxidative stress).