title: A Heme-responsive Regulator Controls Synthesis of Staphyloferrin B in Staphylococcus aureus.
abstract: Staphylococcus aureus possesses a multitude of mechanisms by which it can obtain iron during growth under iron starvation conditions. It expresses an effective heme acquisition system (the iron-regulated surface determinant system), it produces two carboxylate-type siderophores staphyloferrin A and staphyloferrin B (SB), and it expresses transporters for many other siderophores that it does not synthesize. The ferric uptake regulator protein regulates expression of genes encoding all of these systems. Mechanisms of fine-tuning expression of iron-regulated genes, beyond simple iron regulation via ferric uptake regulator, have not been uncovered in this organism. Here, we identify the ninth gene of the sbn operon, sbnI, as encoding a ParB/Spo0J-like protein that is required for expression of genes in the sbn operon from sbnD onward. Expression of sbnD-I is drastically decreased in an sbnI mutant, and the mutant does not synthesize detectable SB during early phases of growth. Thus, SB-mediated iron acquisition is impaired in an sbnI mutant strain. We show that the protein forms dimers and tetramers in solution and binds to DNA within the sbnC coding region. Moreover, we show that SbnI binds heme and that heme-bound SbnI does not bind DNA. Finally, we show that providing exogenous heme to S. aureus growing in an iron-free medium results in delayed synthesis of SB. This is the first study in S. aureus that identifies a DNA-binding regulatory protein that senses heme to control gene expression for siderophore synthesis.
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Laakso
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Cristina L
authors.initials: CL
authors.lastname: Marolda
authors.affiliation: Chemistry.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Pinter
authors.affiliation: Chemistry.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Stillman
authors.affiliation: From the Departments of Microbiology and Immunology and Centre for Human Immunology, University of Western Ontario, London, Ontario N6A 5C1, Canada deh@uwo.ca.
authors.forename: David E
authors.initials: DE
authors.lastname: Heinrichs
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D001483:Base Sequence; D001665:Binding Sites; D053898:Biosynthetic Pathways / Q000187:drug effects / Q000235:genetics; D002951:Citrates / Q000096:biosynthesis*; D004269:DNA, Bacterial / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D056426:Genetic Loci; D006418:Heme / Q000378:metabolism / Q000494:pharmacology*; D007501:Iron / Q000494:pharmacology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D009876:Operon / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D002951:Citrates; D004269:DNA, Bacterial; C083439:staphyloferrin B; D006418:Heme; D007501:Iron
keywords: Staphylococcus aureus (S. aureus); bacterial transcription; biosynthesis; iron metabolism; siderophore