Thiol-based redox regulators in prokaryotes: The relevance of the CXXC motifs

Introduction Prokaryotes must cope with oxidative stress as a result of the normal aerobic metabolism as well as a consequence of exogenous drugs, radiations or even infection-derived host defences. Oxidative stress is responsible for damaging essential cellular structures and biomolecules such as DNA, lipids or proteins. Intriguingly, some transcriptional regulators are capable to sense those redox signals and consequently activate an antioxidant response in the prokaryotic cell. Many of these redox regulators contain reactive cysteines that remain in their thiolate form to increase redox sensitivity towards harmful oxidant species. Reactive cysteines arranged into a redox CXXC motif are considered to play an important role in sensing those redox signals by thiol-based regulators. Those cysteines can either coordinate a metal ion or cofactor such as zinc or iron-sulphur clusters, or remain metal-free to readily participate in thiol-disulphide exchange reactions. In this review, we explore those redox regulators present in several prokaryotes whose activity is based on CXXC motifs, namely Mycobacterium tuberculosis WhiB proteins and RshA, Pyrococcus furiosus SurR, Bacillus subtilis Spx, Streptomyces coelicolor CatR and RsrA and Streptomyces reticuli FurS. Features of FurA from Anabaena PCC7120 FurA evidencing that this protein may work as a CXXC-based redox regulator are also discussed. Conclusion We have analysed the switch on/off response of some redox regulators to oxidative stress, based on their CXXC motifs, and the putative requirement of a cofactor in their redox activity. Finally, we highlight the data that strongly suggest that the global regulator FurA from the cyanobacterium Anabaena PCC 7120 is a novel CXXC-based redox regulator. The presence of two redox active CXXC motifs in FurA, the ability of this regulator to modulate its DNA-binding activity in response to redox environments, together with the existence of FurA molecules in different redox states in Anabaena are in total agreement with our proposal.