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.

Iron availability and oxygen tension regulate the Yersinia Ysc type III secretion system to enable disseminated infection

“…Once Salmonella gains entry into the iron-depleted environment of the host cell, Salmonella no longer requires the SPI-1 T3SS. Iron limitation in deeper tissues would upregulate IscR expression and this should in turn repress expression of hilD and, subsequently, the SPI-1 T3SS [22]. Interestingly, the way in which IscR controls the Salmonella T3SS is distinct from IscR-induced T3SS expression in Y. pseudotuberculosis, which requires its T3SS once the bacteria cross the intestinal epithelium and, presumably, encounter increased oxygen tension or iron limitation under hypoxic conditions.…”

“…One transcription factor known to be controlled by both iron and oxygen is IscR, whose DNA-binding activity is regulated by its association with an iron-sulfur cluster [2Fe-2S] [19][20][21][22]. IscR functions as a sensor of cellular Fe-S cluster status, which in turn is influenced by iron availability and oxidative stress.…”

“…A recent study in Salmonella enterica serovar Typhimurium suggested that IscR leads to induction of the SPI-1 T3SS in response to iron sufficiency. Considering the SPI-1 T3SS is required for Salmonella to invade intestinal epithelial cells, this suggests that Salmonella uses IscR, in conjunction with other factors such as those mentioned above, to sense the gut environment, upregulate the SPI-1 T3SS, and cross the gut barrier [22]. In contrast, enteropathogenic Yersinia need their T3SS after crossing the intestinal barrier.…”

Contrôle de la virulence deSalmonella entericapar la machinerie de biogenèse des centres Fe-S

“…Or, depuis quelques années, beaucoup d'arguments plaident en faveur d'une implication des voies ISC et SUF dans la virulence de nombreuses bactéries, dont S. enterica [4]. Ainsi, récemment, Vergnes et al, une équipe française, ont clairement démontré un nouveau méca-nisme moléculaire impliquant la protéine iron-sulfur cluster regulator (IscR), senseur de centre Fe-S [5].…”

“…L'activation de TGR5 par les acides biliaires secondaires stimule la prolifération et inhibe l'apoptose des cholangiocytes [5]. Au niveau des macrophages, TGR5 limite la production de cytokines pro-inflammatoires [6].…”