Unique Roles of DosT and DosS in DosR Regulon Induction and Mycobacterium tuberculosis Dormancy

Abstract

In Mycobacterium tuberculosis, the sensor kinases DosT and DosS activate the transcriptional regulator DosR, resulting in the induction of the DosR regulon, which is important for anaerobic survival and perhaps latent infection. The individual and collective roles of these sensors have been postulated biochemically, but their roles in vivo have remained unclear. This work demonstrates distinct and additive roles for each sensor during anaerobic dormancy. Both sensors are necessary for wild-type levels of DosR regulon induction, and concomitantly, full induction of the regulon is required for wild-type anaerobic survival. In the anaerobic model, DosT plays an early role, responding to hypoxia. DosT then induces the regulon and with it DosS, which sustains and further induces the regulon. DosT then loses its functionality as oxygen becomes limited, and DosS alone maintains induction of the genes from that point forward. Thus, M. tuberculosis has evolved a system whereby it responds to hypoxic conditions in a stepwise fashion as it enters an anaerobic state.

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

“…Further, it is reported that flavin nucleotides could help to reduce the heme iron of DosS. The heme iron of DosT can withhold the conversion of the Fe 2þ to Fe 3þ in the presence of oxygen [Honaker et al, 2009], suggesting that DosT could play a more important role than DosS in the early phase of hypoxic conditions especially when transferred from aerobic to hypoxic conditions. The C terminus of DosR can bind DNA, and the 54th conserved aspartate is essential for the binding.…”

“…The DosR regulon is regulated by the response regulator DosR. PhoP(Rv0757) can restore the DosR regulon to basal level during aerobic growth too [Gonzalo-Asensio et al, 2008;Honaker et al, 2009].…”

“…DosT responds to hypoxia first, which can autophosphorylate at the 54th aspartate and then transfer phosphate to the aspartate residue of DosR in order to activate it [Roberts et al, 2004], followed by the activation of DosS, a member of the DosR regulon that can further amplify the regulon. As oxygen becomes limited, DosT loses its function, DosS maintains the induction state of DosR regulon alone [Honaker et al, 2009;Kim et al, 2010]. Upon exposure to 0.2% oxygen 2 h, the expression level of DosR regulon in~dosS and~dosT single mutants reduced to 40-45% of the normal level.…”

Transcription factors Rv0081 and Rv3334 connect the early and the enduring hypoxic response of Mycobacterium tuberculosis

“…Based on our results and previous studies, we propose a model for the regulatory network of M. tb in response to hypoxia (Figure 7(a)). In this model, the early hypoxic response of M. tb is mediated by the DosR-DosS/T system, [23,39] which induces the expression of the DosR regulon including Rv0081 . DosR positively regulates its own expression, which forms a positive loop that continuously increases the expression of Rv0081 and other DosR-regulated genes.…”

Dormancy Associated Translation Inhibitor (DATIN/Rv0079) of Mycobacterium tuberculosis interacts with TLR2 and induces proinflammatory cytokine expression

“…A set of 48 genes of dos regulon is up-regulated in stress conditions and presumably play important roles in survival of mycobacteria within the granuloma, under latency. The expression of these genes are controlled by a regulated gene cluster consisting of three genes (Rv3134c/3133c/3132c), among them, DosR (Rv3133c) functions as a cognate response regulator [1][2][3][4][5][6][7][8]. It has been shown that the cellular composition of granuloma is in a dynamic state with respect to oxygen tension [9].…”