Mycobacterium tuberculosisWhiB3: A Novel Iron–Sulfur Cluster Protein That Regulates Redox Homeostasis and Virulence

Abstract

Significance: Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), can persist in a latent state for decades without causing overt disease. Since latent Mtb is refractory to current antimycobacterial drugs, the discovery and characterization of the biological mechanisms controlling the entry, maintenance, and emergence from latent infection is critical to the development of novel clinical therapies. Recent Advances: Recently, Mtb WhiB3, a member of the family of intracellular iron-sulfur (Fe-S) cluster proteins has emerged as a redox sensor and effector molecule controlling several aspects of Mtb virulence. WhiB3 was shown to contain a 4Fe-4S cluster that specifically reacts with important host gases (O 2 and NO), and exogenous and endogenous metabolic signals to maintain redox balance. Notably, the concept of reductive stress emerged from studies on WhiB3. Critical Issues: The detailed mechanism of how WhiB3 functions as an intracellular redox sensor is unknown. Sustaining Mtb redox balance is particularly important since the bacilli encounter a large number of redox stressors during infection, and because several antimycobacterial prodrugs are effective only upon bioreductive activation in the mycobacterial cytoplasm. Future Directions: How Mtb WhiB3 monitors its internal and external surroundings and modulates endogenous oxido-reductive pathways which in turn alter Mtb signal transduction, nucleic acid and protein synthesis, and enzymatic activation, is mostly unexplored. Modern expression, metabolomic and proteomic technologies should provide fresh insights into these yet unanswered questions. Antioxid. Redox Signal. 16, 687-697.

Transcriptional regulation of bacterial virulence gene expression by molecular oxygen and nitric oxide

“…185,[190][191][192] The expression of whiB3 is enhanced in macrophages and the mouse lung, indicating that M. tuberculosis regulates whiB3 expression in response to environmental signals associated with infection; this is supported by the findings that hypoxia and NO induced whiB3 expression. [193][194][195][196] Its role in virulence is clear-mice infected with a whiB3 null mutant showed increased survival.…”

“…Hence WhiB3 senses the redox state of the bacterium via the presence/absence of the iron-sulfur cluster and the propensity of the cysteine residues that ligate the iron-sulfur cluster to form intramolecular disulfide bonds under oxidizing conditions. 185,191 The physiological significance of the NO-reactivity of the WhiB3 iron-sulfur cluster has yet to be established.…”

Bacterial iron–sulfur cluster sensors in mammalian pathogens

“…During infection, M. tuberculosis is exposed to oxygen and NO stress, which influence stability of the WhiB3 [4Fe-4S] cluster 84, 103 . In the presence of these stressors, the [4Fe-4S] cluster is degraded leading to an accumulation of apo-WhiB3.…”

“…In the presence of these stressors, the [4Fe-4S] cluster is degraded leading to an accumulation of apo-WhiB3. Interestingly, this form of WhiB3 is able to undergo further post-translational modifications in response to redox stress, modulating DNA-binding activity 85, 103 . M. tuberculosis experiences redox stress during infection as a result of NADPH production following fatty acid β-oxidation 103, 104 .…”

13. Reactivity of iron-sulfur clusters with nitric oxide

“…In vivo, whiB3 expression is upregulated in response to NO and an acidic extracellular pH. Seminal work by Singh et al [172] showed that [4Fe-4S] WhiB3 was sensitive to NO, with exposure enhancing site specific DNA binding and, in vivo, shifting propionate anabolism in favor of virulence determinants (polyketides, polyacyltrehaloses, sulfolipids, and phthiocerol dimycocerosates) and storage lipids (principally triacylglycerol) [172][173][174]. Remarkably, the WhiB3-dependent production of polyketide virulence determinants, in part, disrupts phagosomal maturation and acidification.…”