Bacterial Transcription Factors against Reactive Oxygen Species

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Overview

By Jiayu Chen

NOX2 complex produces anti-microbial ROS, Yang et al.

Bacteria live in a world full of toxic reactive oxygen species (ROS), including hydrogen peroxide (H₂O₂), superoxide (O₂^-), and hydroxyl radicals. ROS can cause severe damage to all kinds of cell components, including nucleic acids, lipids and proteins . These highly reactive species are generated endogenously by accidental autoxidation of flavoproteins, a group of non-respiratory redox enzymes. Thus, aerobic bacteria have evolved to maintain high concentration of enzymes that keep intracellular ROS below a lethal level. However, various conditions are known to increase these species above such threshold, inflicting oxidative stress to the bacteria, a phenomenon called “oxidative burst.” One of the major scenario is when bacteria encounter ROS generated by the immune system of their host as a defensive weapon.

Anti-bacterial Mitochondrial ROS, Yang et al.

In human, phagocytes including neutrophils use NADPH oxidase 2 (NOX2) complex as one of the major enzyme mediating the immune response by generating antimicrobial ROS. The resultant ROS would be secreted either outside of the cell as a trap to kill bacteria, or into phagolysosome where internalized bacteria would be degraded (Reeve et al., 2002; Brinkmann et al., 2004). Another situation that may happen during bacterial infection is the ROS generated by the mitochondria. Such defensive mechanism is mediated by many signaling molecule in the Toll pathways including several Toll-like receptors (TLRs), tumor necrosis factor receptor-associated factor 6 (TRAF6) and evolutionarily conserved signaling intermediate in Toll pathways (ECSIT). The activation of Toll pathways resulted in increased cellular ROS as well as anti-bacterial pro-inflammatory cytokine reaction in the nucleus. Pro-inflammatory Th1 cytokine IFN-γ is also involved as a transcriptional regulator via activation of estrogen-related receptor α (ERRα) and PPARγ-coactivator-1β (PGC-1β) in the nucleus. Such interaction induces the genes that encode mitochondrial respiratory chain machinery and thus increase cellular ROS concentration .

Anti-bacterial Mitochondrial ROS, Yang et al.

Therefore, bacteria have developed defensive systems to deal with such situations. One mechanism is ROS inducible transcriptional factors that regulate gene expression of a variety of enzymes to respond to the oxidative stress. Three redox-sensitive transcription factors in bacteria have been intensively studied: OxyR and PerR against H₂O₂, and SoxR against O₂^- .
OxyR is induced by H₂O₂ and activated by reversible disulfide bond formation in its active site (Choi et al., 2001). OxyR is widely distributed in Gram-negative bacteria, such as E. coli. The binding of OxyR to DNA generally turns on the gene expression of a large range of oxidative stress defensive enzymes (Zheng et al., 1998). Recent research also has shown that Gram-negative bacteria Vibrio vulnificus, facultative aerobes, contain two OxyR-type regulators with similar sensory mechanism but different sensitivity in order to fine-tune the expression of genes against H₂O₂ pressure (Kim et al., 2014).
PerR is the equivalent H₂O₂ sensor protein in many Gram-positive bacteria, such as Staphylococcus aureus and Bacillus subtilis. When PerR is in its reduced form, its binding to DNA generally serves as an inhibitor of the expression of target genes. PerR is activated by oxidation of its regulatory metal, either Fe²⁺ or Mn²⁺, which leads to conformational change in the protein and dissociation from DNA, thus relieving the inhibition and initiating transcription of H₂O₂ defensive genes (Li and Helmann, 2014).
SoxR is conserved widely in both proteobacteria and actinobacteria with an O₂^- sensitive metal complex in its active site. The binding of SoxR to DNA induces the transcription of a secondary transcription factor, SoxS, which activates a group of enzymes suppressing the level of O₂^- (Greenbert et al., 1990; Tsaneva and Weiss, 1990; Blanchard et al., 2007).

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Defending against hydrogen peroxide (H₂O₂)

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Activation of OxyR. (a) Oxidation of the H₂O₂ sensitive Cysteine residues activate gene transcription. (b) Reaction mechanism of OxyR H₂O₂ sensitivity

Section 2

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Structure of PerR in Bacillus subtilis. (a) holoenzyme (b) demetallated (Manganese removed) enzyme. The orange balls are Zn and the purple ones are Mn

Section 3

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Overall structure of the SoxR–DNA complex in E. coli. The SoxR dimer is shown in a ribbon representation and the DNA fragment appears in a stick model. The DNA-binding domain, dimerization helix, and Fe-S cluster binding domain are shown in blue, magenta, and yellow, respectively. The two iron and two sulfur atoms of the [2Fe-2S] cluster are represented with brown and green spheres, respectively. Watanabe et al., 2008.

References

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2016, Kenyon College.