title: The ChrA-ChrS and HrrA-HrrS signal transduction systems are required for activation of the hmuO promoter and repression of the hemA promoter in Corynebacterium diphtheriae.
abstract: Transcription of the Corynebacterium diphtheriae hmuO gene, which encodes a heme oxygenase involved in heme iron utilization, is activated in a heme- or hemoglobin-dependent manner in part by the two-component system ChrA-ChrS. Mutation of either the chrA or the chrS gene resulted in a marked reduction of hemoglobin-dependent activation at the hmuO promoter in C. diphtheriae; however, it was observed that significant levels of hemoglobin-dependent expression were maintained in the mutants, suggesting that an additional activator is involved in regulation. A BLAST search of the C. diphtheriae genome sequence revealed a second two-component system, encoded by DIP2268 and DIP2267, that shares similarity with ChrS and ChrA, respectively; we have designated these genes hrrS (DIP2268) and hrrA (DIP2267). Analysis of hmuO promoter expression demonstrated that hemoglobin-dependent activity was fully abolished in strains from which both the chrA-chrS and the hrrA-hrrS two-component systems were deleted. Similarly, deletion of the sensor kinase genes chrS and hrrS or the genes encoding both of the response regulators chrA and hrrA also eliminated hemoglobin-dependent activation at the hmuO promoter. We also show that the regulators ChrA-ChrS and HrrA-HrrS are involved in the hemoglobin-dependent repression of the promoter upstream of hemA, which encodes a heme biosynthesis enzyme. Evidence for cross talk between the ChrA-ChrS and HrrA-HrrS systems is presented. In conclusion, these findings demonstrate that the ChrA-ChrS and HrrA-HrrS regulatory systems are critical for full hemoglobin-dependent activation at the hmuO promoter and also suggest that these two-component systems are involved in the complex mechanism of the regulation of heme homeostasis in C. diphtheriae.
authors.affiliation: Laboratory of Respiratory and Special Pathogens, Division of Bacterial, Parasitic, and Allergenic Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Bibb
authors.forename: Carey A
authors.initials: CA
authors.lastname: Kunkle
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schmitt
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003353:Corynebacterium diphtheriae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D003470:Culture Media; D015964:Gene Expression Regulation, Bacterial; D006418:Heme / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D003470:Culture Media; D006454:Hemoglobins; D008565:Membrane Proteins; C073039:ChrA protein, Bacteria; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); C104107:HmuO protein, bacteria; D011494:Protein Kinases