Insights into redox sensing metalloproteins in Mycobacterium tuberculosis

Mycobacterium tuberculosis, the pathogen that causes tuberculosis, has evolved sophisticated mechanisms for evading assault by the human host. This review focuses on M. tuberculosis regulatory metalloproteins that are sensitive to exogenous stresses attributed to changes in the levels of gaseous molecules (i.e., molecular oxygen, carbon monoxide and nitric oxide) to elicit an intracellular response. In particular, we highlight recent developments on the subfamily of Whi proteins, redox sensing WhiB-like proteins that contain iron–sulfur clusters, sigma factors and their cognate anti-sigma factors of which some are zinc-regulated, and the dormancy survival regulon DosS/DosT–DosR heme sensory system. Mounting experimental evidence suggests that these systems contribute to a highly complex and interrelated regulatory network that controls M. tuberculosis biology. This review concludes with a discussion of strategies that M. tuberculosis has developed to maintain redox homeostasis, including mechanisms to regulate endogenous nitric oxide and carbon monoxide levels. Redox stress response in Mycobacterium tuberculosis utilizes metalloproteins to regulate gene expression in response to extracellular gaseous signals, particularly through iron–sulfur cluster-containing Wbl proteins, the DosS/DosT–DosR heme sensory system and σ factors regulated by cognate zinc-dependent anti-σ factors. [Display omitted] •Mycobacterium tuberculosis (Mtb) has evolved strategies to evade human host assault.•Mtb redox stress response utilizes metalloproteins to regulate gene expression.•The Wbl protein family contains iron–sulfur clusters that are sensitive to NO and O2.•The heme cofactor in DosS/DosT senses NO, CO and O2 and regulates DosR activity.•Zn-dependent anti-σ factors regulate σ factor activity in the presence of ROS.