Abstract
Mycobacterium tuberculosis (MTb) is the causative agent of pulmonary tuberculosis (TB). MTb colonizes the human lung, often entering a non-replicating state before progressing to life-threatening active infections. Transcriptional reprogramming is essential for TB pathogenesis. In vitro, Cmr (a member of the CRP/FNR super-family of transcription regulators) bound at a single DNA site to act as a dual regulator of cmr transcription and an activator of the divergent rv1676 gene. Transcriptional profiling and DNA-binding assays suggested that Cmr directly represses dosR expression. The DosR regulon is thought to be involved in establishing latent tuberculosis infections in response to hypoxia and nitric oxide. Accordingly, DNA-binding by Cmr was severely impaired by nitrosation. A cmr mutant was better able to survive a nitrosative stress challenge but was attenuated in a mouse aerosol infection model. The complemented mutant exhibited a ∼2-fold increase in cmr expression, which led to increased sensitivity to nitrosative stress. This, and the inability to restore wild-type behaviour in the infection model, suggests that precise regulation of the cmr locus, which is associated with Region of Difference 150 in hypervirulent Beijing strains of Mtb, is important for TB pathogenesis.
Highlights
Members of the cyclic AMP receptor (CRP)/fumarate nitrate reduction regulator (FNR) super-family of global transcription regulators control a diverse range of bacterial physiological functions
It was concluded that Cmr does not bind cyclic AMP (cAMP) and lacks cofactors that could function as sensory modules
M. bovis BCG Cmr has been associated with cAMP-responsive gene regulation in vivo [10], there is no evidence in favour of direct interaction between cAMP and M. tuberculosis Cmr or M. bovis BCG Cmr (13, unpublished data)
Summary
Members of the cyclic AMP receptor (CRP)/fumarate nitrate reduction regulator (FNR) super-family of global transcription regulators control a diverse range of bacterial physiological functions. Different proteins in this family control aspects of carbon, nitrogen and sulfur metabolism, nitrogen fixation, aerobic and anaerobic respiration, enzymes of aromatic ring degradation and expression of virulence functions [1,2]. Structural analysis has led to the definition of the archetypical CRP fold which is a versatile structure that has evolved so that members of the super-family have differing functions in signal perception, DNA-binding and interactions with RNA polymerase [3]. In different members of the family the signal molecules can be, for example, cyclic AMP (cAMP), oxygen, carbon monoxide, nitric oxide or 2-oxoglutarate.
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