Global Regulation by CsrA and Its RNA Antagonists

Romeo, Tony; Babitzke, Paul

doi:10.1128/microbiolspec.rwr-0009-2017

Cited by 147 publications

(162 citation statements)

References 114 publications

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“…For example, it is known that the downregulation of genes involved in transcription antitermination (nusB, nusG) and Sec translocon subunit E (secE) shows high fitness in presence of λ phage, and are crucial for the phage growth cycle [118][119][120]. lptABC, kdsC, and lpxAC are known to impact outer membrane biogenesis, LPS synthesis and transport [108,109,121,122]; while the RNA binding global regulator CsrA is known to be involved in carbohydrate metabolism and regulation of biofilm [123,124]. Downregulation of these genes likely leads to pleiotropic effects leading to enhanced fitness in the presence of phages.…”

Section: A Crispri Screen Provides Deeper View Of Phage Resistance Dementioning

confidence: 99%

High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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Bacteriophages (phages) are critical players in the dynamics and function of microbial communities and drive processes as diverse as global biogeochemical cycles and human health. Phages tend to be predators finely tuned to attack specific hosts, even down to the strain level, which in turn defend themselves using an array of mechanisms. However, to date, efforts to rapidly and comprehensively identify bacterial host factors important in phage infection and resistance have yet to be fully realized. Here, we globally map the host genetic determinants involved in resistance to 14 phylogenetically diverse double-stranded DNA phages using two model Escherichia coli strains (K-12 and BL21) with known sequence divergence to demonstrate strain-specific differences. Using genome-wide loss-of-function and gain-of-function genetic technologies, we are able to confirm previously described phage receptors as well as uncover a number of previously unknown host factors that confer resistance to one or more of these phages. We uncover differences in resistance factors that strongly align with the susceptibility of K-12 and BL21 to specific phage. We also identify both phage specific mechanisms, such as the unexpected role of cyclic-di-GMP in host sensitivity to phage N4, and more generic defenses, such as the overproduction of colanic acid capsular polysaccharide that defends against a wide array of phages. Our results indicate that host responses to phages can occur via diverse cellular mechanisms. Our systematic and highthroughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phagemediated selection will shape bacterial phenotype and evolution. The results of this study and future efforts to map the phage resistance landscape will lead to new insights into the coevolution of hosts and their phage, which can ultimately be used to design better phage therapeutic treatments and tools for precision microbiome engineering.3 Introduction:

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Section: A Crispri Screen Provides Deeper View Of Phage Resistance Dementioning

confidence: 99%

High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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“…Through molecular mimicry, GlmY is able to sequester RapZ, leaving GlmZ unprocessed (Göpel et al , , ). Sponging of protein or sRNA by decoy RNAs has emerged as a widespread principle in bacterial post‐transcriptional regulation (Sonnleitner & Bläsi, ; Miyakoshi et al , ; Romeo & Babitzke, ). GlmY specifically accumulates and counters GlmZ decay, when GlcN6P levels decrease (Reichenbach et al , ; Khan et al , ).…”

Section: Introductionmentioning

confidence: 99%

Small RNA ‐binding protein RapZ mediates cell envelope precursor sensing and signaling in Escherichia coli

et al. 2020

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The RNA‐binding protein RapZ cooperates with small RNAs (sRNAs) GlmY and GlmZ to regulate the glmS mRNA in Escherichia coli. Enzyme GlmS synthesizes glucosamine‐6‐phosphate (GlcN6P), initiating cell envelope biosynthesis. GlmZ activates glmS expression by base‐pairing. When GlcN6P is ample, GlmZ is bound by RapZ and degraded through ribonuclease recruitment. Upon GlcN6P depletion, the decoy sRNA GlmY accumulates through a previously unknown mechanism and sequesters RapZ, suppressing GlmZ decay. This circuit ensures GlcN6P homeostasis and thereby envelope integrity. In this work, we identify RapZ as GlcN6P receptor. GlcN6P‐free RapZ stimulates phosphorylation of the two‐component system QseE/QseF by interaction, which in turn activates glmY expression. Elevated GlmY levels sequester RapZ into stable complexes, which prevents GlmZ decay, promoting glmS expression. Binding of GlmY also prevents RapZ from activating QseE/QseF, generating a negative feedback loop limiting the response. When GlcN6P is replenished, GlmY is released from RapZ and rapidly degraded. We reveal a multifunctional sRNA‐binding protein that dynamically engages into higher‐order complexes for metabolite signaling.

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“…Microarray data of an X. citri strain harbouring a mutation in the global regulator CsrA (also 82 called RsmA) indicated its involvement in the regulation of over a hundred genes, including 83 the virB operon that encodes the T4SS proteins VirB1-11 (Andrade et al 2014 CsrA (Weilbacher et al 2003;Janssen et al 2018). Production of these small RNAs in E. coli is 96 controlled by several regulatory pathways, including the BarA/UvrY two-component system 97 that responds to molecules such as formate and acetate, the catabolite repression pathway 98 mediated by cAMP-CRP and the stringent response governed by RelA and SpoT-mediated 99 production of (p)ppGpp (Romeo & Babitzke 2018). Furthermore, direct regulation of CsrA 100 copy numbers in E. coli is achieved by five different promoters using at least two different 101 sigma factors (Yakhnin et al 2011).…”

mentioning

confidence: 99%

“…79 Microarray data of an X. citri strain harbouring a mutation in the global regulator CsrA (also 80 called RsmA) indicated its involvement in the regulation of over a hundred genes, including 81 the virB operon that encodes the T4SS proteins VirB1-11 (Andrade et al 2014). CsrA is a 82 pleiotropic regulator linked to the genetic changes during stationary phase growth, biofilm 83 formation, gluconeogenesis and virulence (Romeo & Babitzke 2018). CsrA acts by binding 84 specific mRNA loops in 5' untranslated regions containing the canonical 5'-GGA-3' motif (Liu 85 & Romeo 1997;Holmqvist et al 2016).…”

mentioning

confidence: 99%

Bactericidal Type IV Secretion System Homeostasis in Xanthomonas citri

Cenens

Andrade

Farah

2019

Preprint

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11Several Xanthomonas species have a type IV secretion system (T4SS) that injects a cocktail of 12 antibacterial proteins into neighbouring Gram-negative bacteria, often leading to rapid lysis 13 upon cell contact. This capability represents an obvious fitness benefit since it can eliminate 14 competition while the liberated contents of the lysed bacteria could provide an increase in 15 the local availability of nutrients. However, the production of this Mega Dalton-sized T4SS, 16with over a hundred subunits, also imposes a significant metabolic cost. Here we show that 17 the chromosomal virB operon, which encodes the entirety of structural genes of the T4SS in 18 X. citri, is regulated by the global regulator CsrA. Relieving CsrA repression from the virB 19 operon produced a greater number of T4SSs in the cell envelope and an increased efficiency 20 in contact dependent lysis of target cells. However, this was also accompanied by a 21 physiological cost leading to reduced fitness when in co-culture with wild-type X. citri. We 22show that T4SS production is constitutive despite being downregulated by CsrA. Cells 23 subjected to a wide range of rich and poor growth conditions maintain a constant density of 24 T4SSs in the cell envelope and concomitant interbacterial competitiveness. These results 25show that CsrA provides a constant though partial repression on the virB operon, 26 independent of the tested growth conditions, in this way controlling T4SS-related costs while 27 at the same time maintaining X. citri's aggressive posture when confronted by competitors. 28 29 2

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Global Regulation by CsrA and Its RNA Antagonists

Cited by 147 publications

References 114 publications

High-throughput mapping of the phage resistance landscape inE. coli

High-throughput mapping of the phage resistance landscape inE. coli

Small RNA ‐binding protein RapZ mediates cell envelope precursor sensing and signaling in Escherichia coli

Bactericidal Type IV Secretion System Homeostasis in Xanthomonas citri

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