SigE: A master regulator of Mycobacterium tuberculosis

Abstract

The Extracellular function (ECF) sigma factor SigE is one of the best characterized out of the 13 sigma factors encoded in the Mycobacterium tuberculosis chromosome. SigE is required for blocking phagosome maturation and full virulence in both mice and guinea pigs. Moreover, it is involved in the response to several environmental stresses as surface stress, oxidative stress, acidic pH, and phosphate starvation. Underscoring its importance in M. tuberculosis physiology, SigE is subjected to a very complex regulatory system: depending on the environmental conditions, its expression is regulated by three different sigma factors (SigA, SigE, and SigH) and a two-component system (MprAB). SigE is also regulated at the post-translational level by an anti-sigma factor (RseA) which is regulated by the intracellular redox potential and by proteolysis following phosphorylation from PknB upon surface stress. The set of genes under its direct control includes other regulators, as SigB, ClgR, and MprAB, and genes involved in surface remodeling and stabilization. Recently SigE has been shown to interact with PhoP to activate a subset of genes in conditions of acidic pH. The complex structure of its regulatory network has been suggested to result in a bistable switch leading to the development of heterogeneous bacterial populations. This hypothesis has been recently reinforced by the finding of its involvement in the development of persister cells able to survive to the killing activity of several drugs.

Keywords: Mycobacterium tuberculosis; pathogenesis; regulatory network; sigma factor; stress response.

Figure 1

Structure of the sigE genomic region showing the sigE coding sequence with its 3 promoters and the rseA-htrA-tatB operon. While P2 coincides with the main sigE translational start codon, P3 is internal to sigE coding region. Trancripts from this promoters are translated from the two indicated uncanonical promoters. The two red boxes in correspondence of P1 represent the MprA binding boxes. Created with BioRender.com.

Figure 2

(A) Transcriptional activation of P2. In the presence of unfolded proteins in the periplasm, DnaK releases the extracellular domain of MprB leading to MprA phosphorylation. Phosphorylated MprA binds to its operators turning off P1 and turning on P2; (B) Post translational activation of SigE. In the presence of surface stress PknB phosphorylates RseA, probably due to a transient interference of the interaction between its PASTA domain and Lipid II. Once phosphorylated, RseA is targeted for degradation by the ClpC1P2 protease releasing the active form of SigE. This will favor the induction its regulon which includes clgR, encoding a positive regulator of the clp genes. Created with BioRender.com.

Figure 3

Transcriptional activation of P3. In conditions of oxydative stress, σ^H is released by its antisigma factor RshA. Consequently, it binds the RNAP core enzyme and transcribes the genes belonging to its regulon, including sigE P3. Created with BioRender.com.

Figure 4

Activation of the SigE network in condition of low pH. Low pH induces damages in periplasmic proteins leading to MprA phosphorylation (not shown). Production of ROS due to low pH oxidize RseA, which consequently release SigE which associate with RNAP core enzyme and transcribe its own gene from P2 with the help of MprA. This helps the cell to limit the production of ROS. At later time points or in the absence of SigE activation (as in the MprAB mutant), ROS accumulates leading to the release of σ^H from its anti sigma factor RshA and consequently to the activation of sigE P3. Created with BioRender.com.

Figure 5

The SigE network is activated by different pathways depending on the conditions encountered by the bacteria. Moreover, SigE activity can be modulated at least by three different two component systems. SS, surface stress; AC, acidic pH; OS, oxidative stress; LP, low phosphate; Yyp, hypoxia. Created with BioRender.com.