Interactions of zinc- and redox-signaling pathways

Zinc and cellular oxidants such as reactive oxygen species (ROS) each participate in a multitude of physiological functions. There is considerable overlap between the affected events, including signal transduction. While there is no obvious direct connection between zinc and ROS, mainly because the bivalent cation zinc does not change its oxidation state in biological systems, these are linked by their interaction with sulfur, forming the remarkable triad of zinc, ROS, and protein thiols. First, zinc binds to reduced thiols and can be released upon oxidation. Thereby, redox signals are translated into changes in the free zinc concentration, which can act as zinc signals. Second, zinc affects oxidation of thiols in several ways, directly as well as indirectly. A protein incorporating many of these interactions is metallothionein (MT), which is rich in cysteine and capable of binding up to seven zinc ions in its fully reduced state. Zinc binding is diminished after (partial) oxidation, while thiols show increased reactivity in the absence of bound metal ions. Adding still more complexity, the MT promoter is controlled by zinc (via metal regulatory transcription factor 1 (MTF-1)) as well as redox (via nuclear factor erythroid 2-related factor 2 (NRF2)). Many signaling cascades that are important for cell proliferation or apoptosis contain protein thiols, acting as centers for crosstalk between zinc- and redox-signaling. A prominent example for shared molecular targets for zinc and ROS are active site cysteine thiols in protein tyrosine phosphatases (PTP), their activity being downregulated by oxidation as well as zinc binding. Because zinc binding also protects PTP thiols form irreversible oxidation, there is a multi-faceted reciprocal interaction, illustrating that zinc- and redox-signaling are intricately linked on multiple levels.