Sense and sensor ability: redox-responsive regulators in Listeria monocytogenes

Abstract

Listeria monocytogenes (Lm) is a Gram-positive bacterium that thrives in nature as a saprophyte and in the mammalian host as an intracellular pathogen. Both environments pose potential danger in the form of redox stress. In addition, endogenous reactive oxygen species (ROS) are continuously generated as by-products of aerobic metabolism. Redox stress from ROS can damage proteins, lipids, and DNA, making it highly advantageous for bacteria to evolve mechanisms to sense and detoxify ROS. This review focuses on the five redox-responsive regulators in Lm: OhrR (to sense organic hydroperoxides), PerR (peroxides), Rex (NAD⁺/NADH homeostasis), SpxA1/2 (disulfide stress), and PrfA (redox stress during infection).

Figure 1.. Redox-regulated repressors.

Schematic depicting the functions of OhrR, PerR, and Rex. Red DNA represents specific DNA-binding sequences recognized by each transcriptional repressor. A. Dimerized, reduced OhrR binds to specific DNA sequences and represses downstream genes. OHP stress oxidizes a cysteine residue on each monomer to sulfenic acid (-OH). This can then be S- thiolated by the low-molecular-weight thiols cysteine or glutathione, resulting in nonfunctional protein and derepression of ohrA [42,43]. B. In the absence of stress and in the presence of sufficient metals, PerR binds to DNA and represses expression of target genes [9]. Peroxide induces oxidation of Fe(II)- bound PerR, altering the conformation such that it releases from the DNA and the PerR regulon is derepressed [15]. Oxidized PerR is then targeted for degradation [11]. Dysregulation of the PerR regulon also occurs in conditions of excess Zn(II) or Mn(II) [44]. C. When NAD⁺ concentrations are sufficient, Rex represses target genes by binding a specific DNA sequence, referred to as a ‘Rex box’. However, as NADH increases, it competes with NAD⁺ for binding to Rex and NADH-bound protein does not bind DNA, thereby relieving repression of the Rex regulon [18].

Figure 2.. Redox-regulated activators.

Schematic depicting the functions of SpxA1 and PrfA. A. SpxA1 can activate or repress target genes. In the absence of stress, SpxA1 abundance is kept low by ClpXP-mediated degradation, which requires the protease adaptor protein YjbH [23]. Disulfide stress induces YjbH aggregation, resulting in increased SpxA1 abundance. SpxA1 does not possess DNA-binding activity on its own, but regulates target genes through its interaction with the αCTD of RNA polymerase [45]. B. PrfA is a homodimer that binds to a 14-bp palindromic repeat referred to as a ‘PrfA box’. Reduction of the protein thiols allows PrfA to bind to high-affinity PrfA boxes containing perfect palindromic sequences [32]. During infection, allosteric binding of glutathione to PrfA induces the active conformation that promotes transcription of all PrfA boxes [39].