Review Article The mechanism of redox sensing in Mycobacterium tuberculosis Shabir Ahmad Bhat, Nisha Singh, Abhishek Trivedi, Pallavi Kansal, Pawan Gupta, Ashwani Kumar n Council of Scientific and Industrial Research, Institute of Microbial Technology, Chandigarh 160036, India article info Article history: Received 12 April 2012 Received in revised form 3 August 2012 Accepted 3 August 2012 Available online 11 August 2012 Keywords: Redox homeostasis Redox sensing Virulence DosS DosT DosR WhiB3 Anti-s factors Serine–threonine kinases Metabolic flexibility Free radicals abstract Tuberculosis epidemics have defied constraint despite the availability of effective treatment for the past half-century. Mycobacterium tuberculosis, the causative agent of TB, is continually exposed to a number of redox stressors during its pathogenic cycle. The mechanisms used by Mtb to sense redox stress and to maintain redox homeostasis are central to the success of Mtb as a pathogen. Careful analysis of the Mtb genome has revealed that Mtb lacks classical redox sensors such as FNR, FixL, and OxyR. Recent studies, however, have established that Mtb is equipped with various sophisticated redox sensors that can detect diverse types of redox stress, including hypoxia, nitric oxide, carbon monoxide, and the intracellular redox environment. Some of these sensors, such as heme-based DosS and DosT, are unique to mycobacteria, whereas others, such as the WhiB proteins and anti-s factor RsrA, are unique to actinobacteria. This article provides a comprehensive review of the literature on these redox-sensory modules in the context of TB pathogenesis. & 2012 Elsevier Inc. All rights reserved. Contents Introduction ..................................................................................................... 1626 The role of redox stress in tuberculosis pathogenesis .................................................................... 1626 The role of ROS in tuberculosis pathogenesis ..................................................................... 1626 The role of hypoxia in latency and reactivation ................................................................... 1626 The role of nitric oxide (NO) in tuberculosis pathogenesis .......................................................... 1627 The role of acidic pH stress in tuberculosis pathogenesis ........................................................... 1628 Mtb lacks classical redox sensors .................................................................................... 1628 DosS and DosT: heme-based sensors of redox, hypoxia, NO, and CO ........................................................ 1629 The Dos regulon and the mycobacterial response to hypoxia, NO, and CO .............................................. 1629 The molecular mechanism of redox and gas sensing by DosS and DosT ................................................ 1631 WhiB proteins as iron–sulfur cluster-based sensors...................................................................... 1632 WhiBs as iron–sulfur cluster proteins with protein disulfide reductase activity.......................................... 1632 WhiBs as redox-responsive transcriptional factors ................................................................. 1634 WhiB proteins as virulence and stress response factors ............................................................. 1634 Redox-regulated s factors .......................................................................................... 1634 The role of serine–threonine kinases in redox homeostasis of mycobacterium ................................................. 1636 Concluding remarks ............................................................................................... 1637 Acknowledgments ................................................................................................ 1637 References ...................................................................................................... 1637 Contents lists available at SciVerse ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed Free Radical Biology and Medicine 0891-5849/$ - see front matter & 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.freeradbiomed.2012.08.008 n Corresponding author. Fax: þ91 172 2690585. E-mail address: ashwanik@imtech.res.in (A. Kumar). Free Radical Biology and Medicine 53 (2012) 1625–1641