Integration of a complex regulatory cascade involving the SirA/BarA and Csr global regulatory systems that controls expression of the <i>Salmonella</i> SPI‐1 and SPI‐2 virulence regulons through HilD

Martínez, Luary C.; Yakhnin, Helen; Camacho, Martha I.; Georgellis, Dimitris; Babitzke, Paul; Puente, José L.; Bustamante, Vı́ctor H.

doi:10.1111/j.1365-2958.2011.07674.x

Cited by 136 publications

(190 citation statements)

References 91 publications

(199 reference statements)

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“…UvrY protein was phosphorylated by incubation with 100 mM lithium potassium acetyl-phosphate (SigmaAldrich) for 60 min at room temperature in a buffer containing 50 mM HEPES, 100 mM NaCl, and 10 mM MgCl 2 as described previously (40).…”

Section: Methodsmentioning

confidence: 99%

“…Fluctuations in the levels of these RNAs regulate CsrA activity in response to the environment. Transcription of both csrB and csrC (csrB/C) is activated by the BarA-UvrY two-component signal transduction system (TCS) in response to carboxylic acids such as formate and acetate (3,(36)(37)(38)(39)(40)(41). CsrA indirectly activates transcription of CsrB and CsrC through its effects on BarA-UvrY, creating a negative-feedback loop within the Csr circuitry (37,38,42).…”

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confidence: 99%

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Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli

et al. 2016

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Cyclic AMP (cAMP) and the cAMP receptor protein (cAMP-CRP) and CsrA are the principal regulators of the catabolite repression and carbon storage global regulatory systems, respectively. cAMP-CRP controls the transcription of genes for carbohydrate metabolism and other processes in response to carbon nutritional status, while CsrA binds to diverse mRNAs and regulates translation, RNA stability, and/or transcription elongation. CsrA also binds to the regulatory small RNAs (sRNAs) CsrB and CsrC, which antagonize its activity. The BarA-UvrY two-component signal transduction system (TCS) directly activates csrB and csrC (csrB/C) transcription, while CsrA does so indirectly. We show that cAMP-CRP inhibits csrB/C transcription without negatively regulating phosphorylated UvrY (P-UvrY) or CsrA levels. A crp deletion caused an elevation in CsrB/C levels in the stationary phase of growth and increased the expression of csrB-lacZ and csrClacZ transcriptional fusions, although modest stimulation of CsrB/C turnover by the crp deletion partially masked the former effects. DNase I footprinting and other studies demonstrated that cAMP-CRP bound specifically to three sites located upstream from the csrC promoter, two of which overlapped the P-UvrY binding site. These two proteins competed for binding at the overlapping sites. In vitro transcription-translation experiments confirmed direct repression of csrC-lacZ expression by cAMP-CRP. In contrast, cAMP-CRP effects on csrB transcription may be mediated indirectly, as it bound nonspecifically to csrB DNA. In the reciprocal direction, CsrA bound to crp mRNA with high affinity and specificity and yet exhibited only modest, conditional effects on expression. Our findings are incorporated into an emerging model for the response of Csr circuitry to carbon nutritional status. IMPORTANCECsr (Rsm) noncoding small RNAs (sRNAs) CsrB and CsrC of Escherichia coli use molecular mimicry to sequester the RNA binding protein CsrA (RsmA) away from lower-affinity mRNA targets, thus eliciting major shifts in the bacterial lifestyle. CsrB/C transcription and turnover are activated by carbon metabolism products (e.g., formate and acetate) and by a preferred carbon source (glucose), respectively. We show that cAMP-CRP, a mediator of classical catabolite repression, inhibits csrC transcription by binding to the upstream region of this gene and also inhibits csrB transcription, apparently indirectly. We propose that glucose availability activates pathways for both synthesis and turnover of CsrB/C, thus shaping the dynamics of global signaling in response to the nutritional environment by poising CsrB/C sRNA levels for rapid response.T he Csr (carbon storage regulator) or Rsm (repressor of stationary-phase metabolites) system is a widely conserved bacterial posttranscriptional regulatory system (1-3). Its components, their functions, and the mechanisms by which the central regulator of this system, CsrA or RsmA, affects gene expression have been studied primarily in Gammaproteobacteria (4-6). The...

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Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli

et al. 2016

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“…However, the regulation and function of the Salmonella T3SSs may be more complicated. SPI1 and SPI2, which contribute to inflammation, and the anaerobic respiration pathways that take advantage of inflammation are all regulated by CsrA, as detailed below (98,269).…”

Section: Salmonella Speciesmentioning

confidence: 99%

“…The effects of barA, sirA, csrB, and csrC on SPI1 are mediated through the binding of CsrA to the hilD transcript (269). BarA phosphorylates SirA (73,269), which then binds as a dimer to an 18-bp inverted repeat sequence between positions Ϫ190 and Ϫ173 of csrB and Ϫ168 and Ϫ151 of csrC relative to their transcription start sites (63).…”

Section: Salmonella Speciesmentioning

confidence: 99%

Regulation of Bacterial Virulence by Csr (Rsm) Systems

Vakulskas

Potts

Babitzke

et al. 2015

Microbiol Mol Biol Rev

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SUMMARY Most bacterial pathogens have the remarkable ability to flourish in the external environment and in specialized host niches. This ability requires their metabolism, physiology, and virulence factors to be responsive to changes in their surroundings. It is no surprise that the underlying genetic circuitry that supports this adaptability is multilayered and exceedingly complex. Studies over the past 2 decades have established that the CsrA/RsmA proteins, global regulators of posttranscriptional gene expression, play important roles in the expression of virulence factors of numerous proteobacterial pathogens. To accomplish these tasks, CsrA binds to the 5′ untranslated and/or early coding regions of mRNAs and alters translation, mRNA turnover, and/or transcript elongation. CsrA activity is regulated by noncoding small RNAs (sRNAs) that contain multiple CsrA binding sites, which permit them to sequester multiple CsrA homodimers away from mRNA targets. Environmental cues sensed by two-component signal transduction systems and other regulatory factors govern the expression of the CsrA-binding sRNAs and, ultimately, the effects of CsrA on secretion systems, surface molecules and biofilm formation, quorum sensing, motility, pigmentation, siderophore production, and phagocytic avoidance. This review presents the workings of the Csr system, the paradigm shift that it generated for understanding posttranscriptional regulation, and its roles in virulence networks of animal and plant pathogens.

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“…One such mechanism involves a small (61-aminoacid) protein, named CsrA, acting as a post-transcriptional regulator. Originally discovered as a repressor of glycogen biosynthesis in Escherichia coli (Romeo et al 1993), CsrA was subsequently found to regulate other growth phasedependent processes such as biofilm formation and quorum sensing in E. coli and Vibrio cholerae (Jackson et al 2002;Lenz et al 2005;Wang et al 2005;Yakhnin et al 2011) and host invasion in Salmonella (Altier et al 2000;Lawhon et al 2003;Martinez et al 2011). The CsrA structural homologs RsmA/RsmE perform similar functions in Pseudomonas and Erwinia species, where they participate in the regulation of secondary metabolism Cui et al 1995;Pessi et al 2001;Lapouge et al 2007).…”

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RNA remodeling by bacterial global regulator CsrA promotes Rho-dependent transcription termination

Figueroa‐Bossi¹,

Schwartz²,

Guillemardet³

et al. 2014

Genes Dev.

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RNA-binding protein CsrA is a key regulator of a variety of cellular processes in bacteria, including carbon and stationary phase metabolism, biofilm formation, quorum sensing, and virulence gene expression in pathogens. CsrA binds to bipartite sequence elements at or near the ribosome loading site in messenger RNA (mRNA), most often inhibiting translation initiation. Here we describe an alternative novel mechanism through which CsrA achieves negative regulation. We show that CsrA binding to the upstream portion of the 59 untranslated region of Escherichia coli pgaA mRNA-encoding a polysaccharide adhesin export protein-unfolds a secondary structure that sequesters an entry site for transcription termination factor Rho, resulting in the premature stop of transcription. These findings establish a new paradigm for bacterial gene regulation in which remodeling of the nascent transcript by a regulatory protein promotes Rho-dependent transcription attenuation.

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Integration of a complex regulatory cascade involving the SirA/BarA and Csr global regulatory systems that controls expression of the Salmonella SPI‐1 and SPI‐2 virulence regulons through HilD

Cited by 136 publications

References 91 publications

Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli

Circuitry Linking the Catabolite Repression and Csr Global Regulatory Systems of Escherichia coli

Regulation of Bacterial Virulence by Csr (Rsm) Systems

RNA remodeling by bacterial global regulator CsrA promotes Rho-dependent transcription termination

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