Cmr is a redox-responsive regulator of DosR that contributes to M. tuberculosis virulence

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.

Protein kinase B controls Mycobacterium tuberculosis growth via phosphorylation of the transcriptional regulator Lsr2 at threonine 112

“…Post-translational modifications are common mechanisms for the regulation of DNA binding both in eukaryotes (Bannister and Kouzarides, 2011) and prokaryotes (Dilweg and Dame, 2018). Phosphorylation or nitrosylation of transcriptional regulators abolish DNA binding (Leiba et al, 2014;Smith et al, 2017). H-NS protein, a homologue of Lsr2 in E. coli, has been shown to be acetylated and phosphorylated; however, the precise function of these modifications remains to be characterised (Dilweg and Dame, 2018).…”

AbmR (Rv1265) is a novel transcription factor of Mycobacterium tuberculosis that regulates host cell association and expression of the non‐coding small RNA Mcr11

“…The functional impact of post-translational modification (PTM) of AbmR by phosphorylation is unknown, but PTM of AbmR may feed into an ATP sensing and signaling network. PknH has a demonstrated role in phosphorylating the dormancy survival response regulator (DosR) (Chao et al, 2010), and regulatory overlaps between DosR and Cmr have recently been revealed (Ranganathan et al, 2016;Smith et al, 2017). Decrypting the regulatory overlap of AbmR and cAMP responsive TFs such as CRP Mt and Cmr during infection and persistence will contribute to our understanding of Mtb's adaptation to the host environment.…”

Novel structural features drive DNA binding properties of Cmr, a CRP family protein in TB complex mycobacteria

“…The unique fold of Cmr also indicates a more distant evolutionary relationship with CRP/FNR TFs, as suggested previously by a phylogenetic study ( 6 ). This functional complexity may provide Cmr with the flexibility to simultaneously integrate multiple signals and modulate its DNA interactions in response to different inputs, including interactions with other TFs, such as those reported for DosR ( 26 , 27 ).…”

“…CRP Mt is the closest Mtb ortholog of CRP Ec and is better studied than Cmr ( 19 – 23 ). Both Cmr and CRP Mt exhibit widespread genomic binding associated with the control of large putative regulons ( 24 – 26 ), and deletion of either gene attenuates Mtb virulence in a murine model ( 21 , 27 ). CRP Mt regulates serine metabolism and is required for wild-type (WT) levels of growth in liquid culture and within macrophages ( 20 , 21 , 28 ).…”

“…CRP Mt regulates serine metabolism and is required for wild-type (WT) levels of growth in liquid culture and within macrophages ( 20 , 21 , 28 ). In contrast, Cmr co-regulates genes within the dormancy associated DosR regulon and contributes to nitric oxide sensitivity ( 26 , 27 ) but cmr -deleted mutants are not defective for in vitro growth in nutrient-rich media ( 29 ).…”