Redox sensing by a Rex‐family repressor is involved in the regulation of anaerobic gene expression in Staphylococcus aureus

Abstract

An alignment of upstream regions of anaerobically induced genes in Staphylococcus aureus revealed the presence of an inverted repeat, corresponding to Rex binding sites in Streptomyces coelicolor. Gel shift experiments of selected upstream regions demonstrated that the redox-sensing regulator Rex of S. aureus binds to this inverted repeat. The binding sequence – TTGTGAAW4TTCACAA – is highly conserved in S. aureus. Rex binding to this sequence leads to the repression of genes located downstream. The binding activity of Rex is enhanced by NAD+ while NADH, which competes with NAD+ for Rex binding, decreases the activity of Rex. The impact of Rex on global protein synthesis and on the activity of fermentation pathways under aerobic and anaerobic conditions was analysed by using a rex-deficient strain. A direct regulatory effect of Rex on the expression of pathways that lead to anaerobic NAD+ regeneration, such as lactate, formate and ethanol formation, nitrate respiration, and ATP synthesis, is verified. Rex can be considered a central regulator of anaerobic metabolism in S. aureus. Since the activity of lactate dehydrogenase enables S. aureus to resist NO stress and thus the innate immune response, our data suggest that deactivation of Rex is a prerequisite for this phenomenon.

Redox-Responsive Repressor Rex Modulates Alcohol Production and Oxidative Stress Tolerance in Clostridium acetobutylicum

“…In S. coelicolor and Bacillus subtilis, Rex controls expression of cytochrome bd terminal oxidase and NADH dehydrogenase of the respiratory chain (11,12). The Rex ortholog in Staphylococcus aureus regulates genes involved in anaerobic respiration and fermentation, such as lactate, formate, and ethanol formation and nitrate respiration (13). In Streptococcus mutans and Enterococcus faecalis, Rex has been shown to be involved in regulation of oxidative stress responses and to influence H 2 O 2 accumulation, respectively (14,15).…”

Concerted Up-regulation of Aldehyde/Alcohol Dehydrogenase (ADHE) and Starch in Chlamydomonas reinhardtii Increases Survival under Dark Anoxia

“…In E. coli, for example, ADHE abundance increases up to 10-fold upon exposure to anoxia (54). In Staphylococcus aureus, ADHE is a target of the redox sensing transcriptional regulator Rex, which regulates most genes encoding fermentative enzymes (55). The few data on photosynthetic bacteria (cyanobacteria) also point at a regulation by anoxia: the AdhE transcripts in Synechococcus species in microbial mats (Octopus Spring, Yellowstone National Park) were shown to increase during the evening (56).…”

A Rex Family Transcriptional Repressor Influences H 2 O 2 Accumulation by Enterococcus faecalis

“…Structural studies of Rex factors have identified dinucleotide binding pockets in the C-terminal Rossmann fold domain of the protein. NADH binding in this region leads to a conformational change in a Rex homodimer and a subsequent displacement of Rex from its recognition sites on DNA, leading to derepression of the downstream genes (2)(3)(4).…”

“…For example, changes in availability of oxygen or metabolic activity can influence the relative levels of the dinucleotides NAD ϩ and NADH in the cell (1), and changes in this ratio are detected by the Rex family of transcription factors that are widespread in the genomes of Gram-positive bacteria. Rex factors have been extensively studied in Streptomyces coelicolor, Thermus aquaticus, Thermus thermophilus, Bacillus subtilis, and Staphylococcus aureus (2)(3)(4)(5)(6)(7)(8). Rex factors respond to the cellular NAD ϩ /NADH ratio to modulate expression of genes involved in anaerobiosis, fermentative metabolism, biofilm formation, and oxidative stress (2-4, 7, 9, 10).…”