RshA, an anti-sigma factor that regulates the activity of the mycobacterial stress response sigma factor SigH.
SigH, an alternative sigma factor of Mycobacterium tuberculosis, is a central regulator of the response to oxidative and heat stress. Exposure to these stresses results in increased expression of sigH itself, and of genes encoding additional regulators and effectors of the bacterial response to these stresses. In this work we show that RshA, a protein encoded by a gene in the sigH operon, is an anti-sigma factor of SigH. We demonstrate that RshA binds to SigH in vitro and in vivo. This protein-protein interaction, as well as the ability of RshA to inhibit SigH-dependent transcription, is redox-dependent, with RshA functioning as a negative regulator of SigH activity only under reducing conditions. The interaction of SigH and RshA is also disrupted in vitro by elevated temperature. RshA, a protein of 101 amino acids, contains five conserved cysteine residues of which two appear to be essential for RshA to inhibit SigH activity, suggesting that these cysteines may be important for the redox state dependence of RshA function. Our results indicate that RshA is a sensor that responds to oxidative stress, and also to heat stress, resulting in activation of SigH and expression of the SigH-dependent genes that allow M. tuberculosis to adapt to these stresses.
Song
Taeksun
T
Division of Infectious Diseases, Children's Hospital, Harvard Medical School, Enders 609, 300 Longwood Ave., Boston, MA 02115, USA.
Dove
Simon L
SL
Lee
Kon Ho
KH
Husson
Robert N
RN
D000595:Amino Acid Sequence; D001426:Bacterial Proteins; D001665:Binding Sites; D002352:Carrier Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D003545:Cysteine; D004220:Disulfides / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology*; D009876:Operon; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017386:Sequence Homology, Amino Acid; D012808:Sigma Factor / Q000235:genetics / Q000378:metabolism*; D013696:Temperature; D014158:Transcription, Genetic
D001426:Bacterial Proteins; D002352:Carrier Proteins; D004220:Disulfides; D047908:Intracellular Signaling Peptides and Proteins; C480851:RshA protein, Mycobacterium tuberculosis; C120328:SigH protein, bacteria; D012808:Sigma Factor; D003545:Cysteine