Complex regulation of the global regulatory gene csrA: CsrA‐mediated translational repression, transcription from five promoters by Eσ70 and EσS, and indirect transcriptional activation by CsrA

Yakhnin, Helen; Yakhnin, Alexander V.; Baker, Carol S.; Sineva, Elena V.; Berezin, Igor; Romeo, Tony; Babitzke, Paul

doi:10.1111/j.1365-2958.2011.07723.x

Cited by 79 publications

(131 citation statements)

References 40 publications

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“…In our study, the identification of several GGA trinucleotides in the primary sequence of the 59 UTR of rsmA initially suggested that an autoregulation of RsmA was possible, maybe similar to what was observed for CsrA in E. coli (Yakhnin et al, 2011b). Using a translational rsmA9-9lacZ reporter, we indeed observed that rsmA translation was de-repressed in a DrsmA background.…”

Section: Discussionsupporting

confidence: 84%

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Complex autoregulation of the post-transcriptional regulator RsmA in Pseudomonas aeruginosa

2015

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RsmA is a post-transcriptional RNA-binding protein that acts as a pleiotropic global regulator of mRNAs in the opportunistic pathogen Pseudomonas aeruginosa. Upon binding to its target, RsmA impedes the translation of the mRNA by the ribosome. The RsmA regulon affects over 500 genes, many of which have been identified as important in the pathogenicity of P. aeruginosa. Whilst the regulatory function of RsmA is relatively well characterized, the genetic regulation of rsmA itself at the transcriptional and translational levels remains poorly understood. Here, we show that RsmA is capable of self-regulation through an unorthodox mechanism. This regulation occurs via direct interaction of the protein with an RsmA-binding site located in the early portion of its coding sequence. To the best of our knowledge this is the first report of such an unusual regulation in pseudomonads.

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Section: Discussionsupporting

confidence: 84%

“…The genetic regulation of csrA, coding for the RsmA homologue in Escherichia coli, is complex and dependent on the presence of multiple promoters that are activated at different stages during cell growth. Interestingly, CsrA negatively controls its translation by directly binding to its own mRNA (Yakhnin et al, 2011b).…”

Section: Introductionmentioning

confidence: 99%

Complex autoregulation of the post-transcriptional regulator RsmA in Pseudomonas aeruginosa

2015

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“…We next probed the architecture of the native CsrA cascade using the synthetic CsrA system as a benchmark. Specifically, we sought to determine whether putative transcriptional and translational feedback loops described in the native system affect signaling dynamics under our experimental conditions (7,23). Feedback is known to influence signaling dynamics (1) and CsrA has been reported to (i) positively and negatively regulate its own expression via mechanisms that have not been fully elucidated (23), (ii) inhibit its own activity by increasing transcription of CsrB and CsrC (10,24), and (iii) inhibit its own activity by decreasing CsrD production, which increases CsrB (25).…”

Section: Resultsmentioning

confidence: 99%

Rapid and robust signaling in the CsrA cascade via RNA–protein interactions and feedback regulation

Adamson

Lim

2013

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial survival requires the rapid propagation of signals through gene networks during stress, but how this is achieved is not well understood. This study systematically characterizes the signaling dynamics of a cascade of RNA-protein interactions in the CsrA system, which regulates stress responses and biofilm formation in Escherichia coli. Noncoding RNAs are at the center of the CsrA system; target mRNAs are bound by CsrA proteins that inhibit their translation, CsrA proteins are sequestered by CsrB noncoding RNAs, and the degradation of CsrB RNAs is increased by CsrD proteins. Here, we show using in vivo experiments and quantitative modeling that the CsrA system integrates three strategies to achieve rapid and robust signaling. These strategies include: (i) the sequestration of stable proteins by noncoding RNAs, which rapidly inactivates protein activity; (ii) the degradation of stable noncoding RNAs, which enables their rapid removal; and (iii) a negative-feedback loop created by CsrA repression of CsrD production, which reduces the time for the system to achieve steady state. We also demonstrate that sequestration in the CsrA system results in signaling that is robust to growth rates because it does not rely on the slow dilution of molecules via cell division; therefore, signaling can occur even during growth arrest induced by starvation or antibiotic treatment.gene circuit | reverse engineering | synthetic biology | systems biology

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confidence: 99%

“…In E. coli, csrA is transcribed from five promot-ers using two different sigma factors (34). Furthermore, CsrA directly represses its own translation while indirectly activating its transcription (34). CsrA activity is antagonized by the noncoding small RNAs (sRNAs) CsrB and CsrC, which contain multiple CsrA binding sites that allow them to sequester this protein (35,36).…”

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confidence: 99%

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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Complex regulation of the global regulatory gene csrA: CsrA‐mediated translational repression, transcription from five promoters by Eσ⁷⁰ and Eσ^S, and indirect transcriptional activation by CsrA

Cited by 79 publications

References 40 publications

Complex autoregulation of the post-transcriptional regulator RsmA in Pseudomonas aeruginosa

Complex autoregulation of the post-transcriptional regulator RsmA in Pseudomonas aeruginosa

Rapid and robust signaling in the CsrA cascade via RNA–protein interactions and feedback regulation

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

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