Virulence Factor SenX3 Is the Oxygen-Controlled Replication Switch ofMycobacterium tuberculosis

Abstract

Aim: Morphogenetic switching between the replicating and nonreplicating states of Mycobacterium tuberculosis is regulated by oxygen, nitric oxide, and carbon monoxide levels. The mechanisms by which M. tuberculosis senses these diatomic gases remain poorly understood. In this study, we have examined whether virulence factor SenX3 plays any role in oxygen sensing. Results: In this study, we demonstrate that the virulence factor SenX3 is a heme protein that acts as a three-way sensor with three levels of activity. The oxidation of SenX3 heme by oxygen leads to the activation of its kinase activity, whereas the deoxy-ferrous state confers a moderate kinase activity. The binding of nitric oxide and carbon monoxide inhibits kinase activity. Consistent with these biochemical properties, the SenX3 mutant of M. tuberculosis is capable of attaining a nonreplicating persistent state in response to hypoxic stress, but its regrowth on the restoration of ambient oxygen levels is significantly attenuated compared with the wild-type and the complemented mutant strains. Furthermore, the presence of signaling concentrations of nitric oxide and carbon monoxide was able to inhibit the regrowth of M. tuberculosis in response to ambient oxygen levels. Innovation and Conclusions: Evidence presented in this study delineates a plausible mechanism explaining the oxygen-induced reactivation of tuberculosis diseases in humans after many years of latent infection. Furthermore, this study implicates nitric oxide and carbon monoxide in the inhibition of mycobacterial growth from the nonreplicating state. Antioxid. Redox Signal. 22,[603][604][605][606][607][608][609][610][611][612][613]

Imaging the NADH:NAD+ Homeostasis for Understanding the Metabolic Response of Mycobacterium to Physiologically Relevant Stresses

“…Rex is a transcription factor that regulates several genes involved in respiration including the cydABCD and rex-hemACD operons (Brekasis and Paget, 2003). Although a Rex homolog has not yet been described in Mtb, but Mtb uses a response regulator RegX3 that regulates expression of cydABCD (Roberts et al, 2011) and is responsive to oxygen levels (Singh and Kumar, 2015). Furthermore, accumulation of NADH leads to the induction of PknG, which activates the redox homeostatic system of Mycobacterium to regulate biofilm formation and augment survival of Mtb in macrophages (Wolff et al, 2015).…”

The histidine kinase PdtaS is a cyclic di-GMP binding metabolic sensor that controls mycobacterial adaptation to nutrient deprivation

“…Additionally, due to the great diversity of signals sensed by TCSs despite having a fixed set of domain architectures in their sensory domains, the nature of ligands that bind to the SKs are not readily apparent from the structure of their sensory domains (29). Currently, only two SKs DevS and SenX3 have known ligands and characterized mechanisms of activation (30, 31). This is essential as in order to identify the ideal TCS drug target, the details about what TCS SKs sense and how signal transduction occurs need to be elucidated.…”

Bioenergetics of Mycobacterium: An Emerging Landscape for Drug Discovery

“…Although the affinity of the Mtb bd -oxidase for oxygen has not been determined, its expression is also induced during hypoxia [ 65 ]. The expression of cydAB is regulated by a SenX3-RegX3 two-component system [ 85 ], which also acts as an oxygen-controlled replication switch in Mtb [ 86 ]. It was recently demonstrated that Mtb cydAB mutants are sensitive to H 2 O 2 and antibiotic stress [ 87 ].…”