The Impact of 18 Ancestral and Horizontally-Acquired Regulatory Proteins upon the Transcriptome and sRNA Landscape of Salmonella enterica serovar Typhimurium

Colgan, Aoife; Kröger, Carsten; Diard, Médéric; Hardt, Wolf‐Dietrich; Puente, José L.; Sivasankaran, Sathesh K; Hokamp, Karsten; Hinton, Jay C. D.

doi:10.1371/journal.pgen.1006258

Cited by 118 publications

(153 citation statements)

References 119 publications

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“…Anaerobic activation of fnrS is mainly dependent on Fnr, but is also affected by ArcA and CRP (Durand and Storz, ). It has been reported that Fur, the ferric uptake regulator, also affects fnrS expression (Colgan et al , ). Fur is known to positively regulate HilD expression.…”

Section: Resultsmentioning

confidence: 99%

Oxygen‐dependent regulation of SPI1 type three secretion system by small RNAs in Salmonella enterica serovar Typhimurium

Kim

Golubeva

Vanderpool

et al. 2018

Molecular Microbiology

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Summary Salmonella Typhimurium induces inflammatory diarrhea and uptake into intestinal epithelial cells using the Salmonella pathogenicity island 1 (SPI1) type III secretion system (T3SS). Three AraC‐like regulators, HilD, HilC and RtsA, form a feed‐forward regulatory loop that activates transcription of hilA, encoding the activator of the T3SS structural genes. Many environmental signals and regulatory systems are integrated into this circuit to precisely regulate SPI1 expression. A subset of these regulatory factors affects translation of hilD, but the mechanisms are poorly understood. Here, we identified two sRNAs, FnrS and ArcZ, which repress hilD translation, leading to decreased production of HilA. FnrS and ArcZ are oppositely regulated in response to oxygen, one of the key environmental signals affecting expression of SPI1. Mutational analysis demonstrates that FnrS and ArcZ bind to the hilD mRNA 5′ UTR, resulting in translational repression. Deletion of fnrS led to increased HilD production under low‐aeration conditions, whereas deletion of arcZ abolished the regulatory effect on hilD translation aerobically. The fnrS arcZ double mutant has phenotypes in a mouse oral infection model consistent with increased expression of SPI1. Together, these results suggest that coordinated regulation by these two sRNAs maximizes HilD production at an intermediate level of oxygen.

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Section: Resultsmentioning

confidence: 99%

Oxygen‐dependent regulation of SPI1 type three secretion system by small RNAs in Salmonella enterica serovar Typhimurium

Kim

Golubeva

Vanderpool

et al. 2018

Molecular Microbiology

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“…Their genes (Argaman et al, 2001;Wassarman et al, 2001;Vogel et al, 2003) are transcriptionally activated by the OmpR-EnvZ two-component system, e.g., under high osmolarity conditions (Guillier & Gottesman, 2006;Brosse et al, 2016). OmrA, but not OmrB, is additionally under the control of the stress sigma factor r s (rpoS; Lévi-Meyrueis et al, 2014;Peano et al, 2015;Colgan et al, 2016). Both sRNAs associate with Hfq in vitro (Holmqvist et al, 2010) and in vivo (Wassarman et al, 2001;Zhang et al, 2003;Chao et al, 2012;Tree et al, 2014;Holmqvist et al, 2016); the sRNAs are destabilized in Δhfq cells (Holmqvist et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Hfq‐dependent mRNA unfolding promotes sRNA ‐based inhibition of translation

et al. 2019

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Small RNAs post‐transcriptionally regulate many processes in bacteria. Base‐pairing of sRNAs near ribosome‐binding sites in mRNAs inhibits translation, often requiring the RNA chaperone Hfq. In the canonical model, Hfq simultaneously binds sRNAs and mRNA targets to accelerate pairing. Here, we show that the Escherichia coli sRNAs OmrA and OmrB inhibit translation of the diguanylate cyclase DgcM (previously: YdaM), a player in biofilm regulation. In OmrA/B repression of dgcM, Hfq is not required as an RNA interaction platform, but rather unfolds an inhibitory RNA structure that impedes OmrA/B binding. This restructuring involves distal face binding of Hfq and is supported by RNA structure mapping. A corresponding mutant protein cannot support inhibition in vitro and in vivo; proximal and rim mutations have negligible effects. Strikingly, OmrA/B‐dependent translational inhibition in vitro is restored, in complete absence of Hfq, by a deoxyoligoribonucleotide that base‐pairs to the biochemically mapped Hfq site in dgcM mRNA. We suggest that Hfq‐dependent RNA structure remodeling can promote sRNA access, which represents a mechanism distinct from an interaction platform model.

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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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The Impact of 18 Ancestral and Horizontally-Acquired Regulatory Proteins upon the Transcriptome and sRNA Landscape of Salmonella enterica serovar Typhimurium

Cited by 118 publications

References 119 publications

Oxygen‐dependent regulation of SPI1 type three secretion system by small RNAs in Salmonella enterica serovar Typhimurium

Oxygen‐dependent regulation of SPI1 type three secretion system by small RNAs in Salmonella enterica serovar Typhimurium

Hfq‐dependent mRNA unfolding promotes sRNA ‐based inhibition of translation

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

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