Regulation of the SigH stress response regulon by an essential protein kinase in Mycobacterium tuberculosis

Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13105-10. doi: 10.1073/pnas.0801143105. Epub 2008 Aug 26.

Abstract

SigH is a key regulator of an extensive transcriptional network that responds to oxidative, nitrosative, and heat stresses in Mycobacterium tuberculosis, and this sigma factor is required for virulence in animal models of infection. SigH is negatively regulated by RshA, its cognate anti-sigma factor, which functions as a stress sensor and redox switch. While RshA provides a direct mechanism for sensing stress and activating transcription, bacteria use several types of signal transduction systems to sense the external environment. M. tuberculosis encodes several serine-threonine protein kinase signaling molecules, 2 of which, PknA and PknB, are essential and have been shown to regulate cell morphology and cell wall synthesis. In this work, we demonstrate that SigH and RshA are phosphorylated in vitro and in vivo by PknB. We show that phosphorylation of RshA, but not SigH, interferes with the interaction of these 2 proteins in vitro. Consistent with this finding, negative regulation of SigH activity by RshA in vivo is partially relieved in strains in which pknB is over-expressed, resulting in increased resistance to oxidative stress. These findings demonstrate an interaction between the signaling pathways mediated by PknB and the stress response regulon controlled by SigH. The intersection of these apparently discrete regulatory systems provides a mechanism by which limited activation of the SigH-dependent stress response in M. tuberculosis can be achieved. Coordination of the PknB and SigH regulatory pathways through phosphorylation of RshA may lead to adaptive responses that are important in the pathogenesis of M. tuberculosis infection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Bacterial Proteins / metabolism*
  • Disulfides / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mycobacterium tuberculosis / cytology
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / enzymology*
  • Mycobacterium tuberculosis / genetics*
  • Phosphoric Monoester Hydrolases / pharmacology
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein-Serine-Threonine Kinases / metabolism*
  • Regulon / genetics*
  • Sigma Factor / metabolism*

Substances

  • Bacterial Proteins
  • Disulfides
  • Intracellular Signaling Peptides and Proteins
  • RshA protein, Mycobacterium tuberculosis
  • SigH protein, bacteria
  • Sigma Factor
  • PknB protein, Mycobacterium tuberculosis
  • Protein-Serine-Threonine Kinases
  • Phosphoric Monoester Hydrolases