title: The iron-sulfur cluster sensor IscR is a negative regulator of Spi1 type III secretion system in Salmonella enterica.
abstract: Iron-sulfur (Fe-S)-containing proteins contribute to various biological processes, including redox reactions or regulation of gene expression. Living organisms have evolved by developing distinct biosynthetic pathways to assemble these clusters, including iron sulfur cluster (ISC) and sulfur mobilization (SUF). Salmonella enterica serovar Typhimurium is an intracellular pathogen responsible for a wide range of infections, from gastroenteritis to severe systemic diseases. Salmonella possesses all known prokaryotic systems to assemble Fe-S clusters, including ISC and SUF. Because iron starvation and oxidative stress are detrimental for Fe-S enzyme biogenesis and because such environments are often met by Salmonella during its intracellular life, we investigated the role of the ISC and SUF machineries during the course of the infection. The iscU mutant, which is predicted to have no ISC system functioning, was found to be defective for epithelial cell invasion and for mice infection, whereas the sufBC mutant, which is predicted to have no SUF system functioning, did not present any defect. Moreover, the iscU mutant was highly impaired in the expression of Salmonella pathogenicity island 1 (Spi1) type III secretion system that is essential for the first stage of Salmonella infection. The Fe-S cluster sensor IscR, a transcriptional regulator matured by the ISC machinery, was shown to bind the promoter of hilD, which encodes the master regulator of Spi1. IscR was also demonstrated to repress hilD and subsequently Spi1 gene expression, consistent with the observation that an IscR mutant is hyper-invasive in epithelial cells. Collectively, our findings indicate that the ISC machinery plays a central role in Salmonella virulence through the ability of IscR to down-regulate Spi1 gene expression. At a broader level, this model illustrates an adaptive mechanism used by bacterial pathogens to modulate their infectivity according to iron and oxygen availability.
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Vergnes
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Julie P M
authors.initials: JP
authors.lastname: Viala
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Rabah
authors.initials: R
authors.lastname: Ouadah-Tsabet
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Bérengère
authors.initials: B
authors.lastname: Pocachard
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Loiseau
authors.affiliation: Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Méresse
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Barras
authors.affiliation: Aix Marseille Université, CNRS, LCB UMR, 7283, IMM, Marseille, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Aussel
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000502:physiology*; D001483:Base Sequence; D001665:Binding Sites; D004269:DNA, Bacterial / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D015870:Gene Expression; D015964:Gene Expression Regulation, Bacterial; D006367:HeLa Cells; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D000067996:RAW 264.7 Cells; D019779:Salmonella enterica / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D000069296:Type III Secretion Systems / Q000235:genetics* / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D007506:Iron-Sulfur Proteins; D014157:Transcription Factors; D000069296:Type III Secretion Systems