In silico clustering of Salmonella global gene expression data reveals novel genes co-regulated with the SPI-1 virulence genes through HilD

Martínez-Flores, Irma; Pérez-Morales, Deyanira; Sánchez-Pérez, Mishael; Paredes-Amaya, Claudia; Collado‐Vides, Julio; Salgado, Heladia

doi:10.1038/srep37858

Cited by 22 publications

(17 citation statements)

References 80 publications

(132 reference statements)

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“…Typhimurium. HilD acts as a regulatory hub for virulence coordinating the expression of several virulence factors encoded inside and outside SPI-1 [18,28,40–42]. Indeed, in this report we provide further corroboration of the role of HilD in regulating SPI-2 gene expression.…”

Section: Discussionsupporting

confidence: 76%

Gre factors-mediated control of hilD transcription is essential for the invasion of epithelial cells by Salmonella enterica serovar Typhimurium

et al. 2017

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The invasion of epithelial cells by Salmonella enterica serovar Typhimurium is a very tightly regulated process. Signaling cascades triggered by different environmental and physiological signals converge to control HilD, an AraC regulator that coordinates the expression of several virulence factors. The expression of hilD is modulated at several steps of the expression process. Here, we report that the invasion of epithelial cells by S. Typhimurium strains lacking the Gre factors, GreA and GreB, is impaired. By interacting with the RNA polymerase secondary channel, the Gre factors prevent backtracking of paused complexes to avoid arrest during transcriptional elongation. Our results indicate that the Gre factors are required for the expression of the bacterial factors needed for epithelial cell invasion by modulating expression of HilD. This regulation does not occur at transcription initiation and depends on the capacity of the Gre factors to prevent backtracking of the RNA polymerase. Remarkably, genetic analyses indicate that the 3’-untranslated region (UTR) of hilD is required for Gre-mediated regulation of hilD expression. Our data provide new insight into the complex regulation of S. Typhimurium virulence and highlight the role of the hilD 3’-UTR as a regulatory motif.

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Section: Discussionsupporting

confidence: 76%

Gre factors-mediated control of hilD transcription is essential for the invasion of epithelial cells by Salmonella enterica serovar Typhimurium

et al. 2017

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“…HilC and RtsA are AraC-like transcriptional regulators that bind the same DNA sequence recognized by HilD; HilC is encoded within SPI-1, whereas RtsA is encoded in another island. HilD also controls the expression of many other virulence genes located outside SPI-1, including acquired and ancestral genes, directly, or indirectly through HilA, InvF or other regulators (12,(17)(18)(19)(20)(21)(22)(23)(24)(25). In agreement with its role as a master transcriptional regulator for a high number of genes, the expression, concentration and activity of HilD is tightly controlled.…”

Section: Introductionmentioning

confidence: 99%

The Hcp-like protein HilE inhibits homodimerization and DNA binding of the virulence-associated transcriptional regulator HilD in Salmonella

Paredes-Amaya

Valdés-García

Juárez-González

et al. 2018

Journal of Biological Chemistry

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HilD is an AraC-like transcriptional regulator that plays a central role in Salmonella virulence. HilD controls the expression of the genes within the Salmonella pathogenicity island 1 (SPI-1) and of several genes located outside SPI-1, which are mainly required for Salmonella invasion of host cells. The expression, amount and activity of HilD are tightly controlled by the activities of several factors. The HilE protein represses the expression of the SPI-1 genes through its interaction with HilD; however, the mechanism by which HilE affects HilD is unknown. In this study, we used genetic and biochemical assays revealing how HilE controls the transcriptional activity of HilD. We found that HilD needs to assemble in homodimers to induce expression of its target genes. Our results further indicated that HilE individually interacts with each the central and the C-terminal HilD regions, mediating dimerization and DNA binding, respectively. We also observed that these interactions consistently inhibit HilD dimerization and DNA binding. Interestingly, a computational analysis revealed that HilE shares sequence and structural similarities with Hcp proteins, which act as structural components of type 6 secretion systems in Gram-negative bacteria. In conclusion, our results uncover the molecular mechanism by which the Hcp-like protein HilE controls dimerization and DNA binding of the virulence-promoting transcriptional regulator HilD. Our findings may indicate that HilE's activity represents a functional adaptation during the evolution of Salmonella pathogenicity.

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“…In a previous study, we identified a set of novel genes that are co-expressed with the SPI-1 genes in S . Typhimurium, by an in silico global expression analysis 42 . The characterization of some of these genes revealed a strong link between the co-expression with SPI-1 and the regulation by HilD.…”

Section: Resultsmentioning

confidence: 99%

“…Typhimurium. The expression of genes known to be directly controlled by HiD, such as hilA , can be induced in E. coli K-12 when HilD is present 42 . Therefore, to further test if HilD regulates grhD1 indirectly, the activity of the grhD1-cat fusion was determined in the E. coli MC4100 strain carrying the pK6-HilD plasmid, grown in LB.…”

Section: Resultsmentioning

confidence: 99%

HilD and PhoP independently regulate the expression of grhD1, a novel gene required for Salmonella Typhimurium invasion of host cells

Banda

López

Manzo

et al. 2018

Sci Rep

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When Salmonella is grown in the nutrient-rich lysogeny broth (LB), the AraC-like transcriptional regulator HilD positively controls the expression of genes required for Salmonella invasion of host cells, such as the Salmonella pathogenicity island 1 (SPI-1) genes. However, in minimal media, the two-component system PhoP/Q activates the expression of genes necessary for Salmonella replication inside host cells, such as the SPI-2 genes. Recently, we found that the SL1344_1872 hypothetical gene, located in a S. Typhimurium genomic island, is co-expressed with the SPI-1 genes. In this study we demonstrate that HilD induces indirectly the expression of SL1344_1872 when S. Typhimurium is grown in LB; therefore, we named SL1344_1872 as grhD1 for gene regulated by HilD. Furthermore, we found that PhoP positively controls the expression of grhD1, independently of HilD, when S. Typhimurium is grown in LB or N-minimal medium. Moreover, we demonstrate that the grhD1 gene is required for the invasion of S. Typhimurium into epithelial cells, macrophages and fibroblasts, as well as for the intestinal inflammatory response caused by S. Typhimurium in mice. Thus, our results reveal a novel virulence factor of Salmonella, whose expression is positively and independently controlled by the HilD and PhoP transcriptional regulators.

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In silico clustering of Salmonella global gene expression data reveals novel genes co-regulated with the SPI-1 virulence genes through HilD

Cited by 22 publications

References 80 publications

Gre factors-mediated control of hilD transcription is essential for the invasion of epithelial cells by Salmonella enterica serovar Typhimurium

Gre factors-mediated control of hilD transcription is essential for the invasion of epithelial cells by Salmonella enterica serovar Typhimurium

The Hcp-like protein HilE inhibits homodimerization and DNA binding of the virulence-associated transcriptional regulator HilD in Salmonella

HilD and PhoP independently regulate the expression of grhD1, a novel gene required for Salmonella Typhimurium invasion of host cells

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