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      Regulation of Hfq by the RNA CrcZ in Pseudomonas aeruginosa Carbon Catabolite Repression

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      PLoS Genetics
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          Abstract

          Carbon Catabolite repression (CCR) allows a fast adaptation of Bacteria to changing nutrient supplies. The Pseudomonas aeruginosa (PAO1) catabolite repression control protein (Crc) was deemed to act as a translational regulator, repressing functions involved in uptake and utilization of carbon sources. However, Crc of PAO1 was recently shown to be devoid of RNA binding activity. In this study the RNA chaperone Hfq was identified as the principle post-transcriptional regulator of CCR in PAO1. Hfq is shown to bind to A-rich sequences within the ribosome binding site of the model mRNA amiE, and to repress translation in vitro and in vivo. We further report that Crc plays an unknown ancillary role, as full-fledged repression of amiE and other CCR-regulated mRNAs in vivo required its presence. Moreover, we show that the regulatory RNA CrcZ, transcription of which is augmented when CCR is alleviated, binds to Hfq with high affinity. This study on CCR in PAO1 revealed a novel concept for Hfq function, wherein the regulatory RNA CrcZ acts as a decoy to abrogate Hfq-mediated translational repression of catabolic genes and thus highlights the central role of RNA based regulation in CCR of PAO1.

          Author Summary

          Carbon assimilation in Bacteria is governed by a mechanism known as carbon catabolite repression (CCR). In contrast to several other bacterial clades CCR in Pseudomonas species appears to be primarily regulated at the post-transcriptional level. In this study, we have identified the RNA chaperone Hfq as the principle post-transcriptional regulator of CCR in P. aeruginosa (PAO1). Hfq is shown to act as a translational regulator and to prevent ribosome loading through binding to A-rich sequences within the ribosome binding site of mRNAs, which encode enzymes involved in carbon utilization. It has been previously shown that the synthesis of the RNA CrcZ is augmented in the presence of non-preferred carbon sources. Here, we show that the CrcZ RNA binds to and sequesters Hfq, which in turn abrogates Hfq-mediated translational repression of mRNAs, the encoded functions of which are required for the breakdown of non-preferred carbon sources. This novel mechanistic twist on Hfq function not only highlights the central role of RNA based regulation in CCR of PAO1 but also broadens the view of Hfq-mediated post-transcriptional mechanisms.

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          Most cited references53

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          Adaptation of Pseudomonas aeruginosa to the cystic fibrosis airway: an evolutionary perspective.

          The airways of patients with cystic fibrosis (CF) are nearly always infected with many different microorganisms. This environment offers warm, humid and nutrient-rich conditions, but is also stressful owing to frequent antibiotic therapy and the host immune response. Pseudomonas aeruginosa is commonly isolated from the airways of patients with CF, where it most often establishes chronic infections that usually persist for the rest of the lives of the patients. This bacterium is a major cause of mortality and morbidity and has therefore been studied intensely. Here, we discuss how P. aeruginosa evolves from a state of early, recurrent intermittent colonization of the airways of patients with CF to a chronic infection state, and how this process offers opportunities to study bacterial evolution in natural environments. We believe that such studies are valuable not only for our understanding of bacterial evolution but also for the future development of new therapeutic strategies to treat severe chronic infections.
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            Carbon catabolite repression in Pseudomonas : optimizing metabolic versatility and interactions with the environment.

            Metabolically versatile free-living bacteria have global regulation systems that allow cells to selectively assimilate a preferred compound among a mixture of several potential carbon sources. This process is known as carbon catabolite repression (CCR). CCR optimizes metabolism, improving the ability of bacteria to compete in their natural habitats. This review summarizes the regulatory mechanisms responsible for CCR in the bacteria of the genus Pseudomonas, which can live in many different habitats. Although the information available is still limited, the molecular mechanisms responsible for CCR in Pseudomonas are clearly different from those of Enterobacteriaceae or Firmicutes. An understanding of the molecular mechanisms underlying CCR is important to know how metabolism is regulated and how bacteria degrade compounds in the environment. This is particularly relevant for compounds that are degraded slowly and accumulate, creating environmental problems. CCR has a major impact on the genes involved in the transport and metabolism of nonpreferred carbon sources, but also affects the expression of virulence factors in several bacterial species, genes that are frequently directed to allow the bacterium to gain access to new sources of nutrients. Finally, CCR has implications in the optimization of biotechnological processes such as biotransformations or bioremediation strategies.
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              Gac/Rsm signal transduction pathway of gamma-proteobacteria: from RNA recognition to regulation of social behaviour.

              In many gamma-proteobacteria, the conserved GacS/GacA (BarA/UvrY) two-component system positively controls the expression of one to five genes specifying small RNAs (sRNAs) that are characterized by repeated unpaired GGA motifs but otherwise appear to belong to several independent families. The GGA motifs are essential for binding small, dimeric RNA-binding proteins of a single conserved family designated RsmA (CsrA). These proteins, which also occur in bacterial species outside the gamma-proteobacteria, act as translational repressors of certain mRNAs when these contain an RsmA/CsrA binding site at or near the Shine-Dalgarno sequence plus additional binding sites located in the 5' untranslated leader mRNA. Recent structural data have established that the RsmA-like protein RsmE of Pseudomonas fluorescens makes specific contacts with an RNA consensus sequence 5'-(A)/(U)CANGGANG(U)/(A)-3' (where N is any nucleotide). Interaction with an RsmA/CsrA protein promotes the formation of a short stem supporting an ANGGAN loop. This conformation hinders access of 30S ribosomal subunits and hence translation initiation. The output of the Gac/Rsm cascade varies widely in different bacterial species and typically involves management of carbon storage and expression of virulence or biocontrol factors. Unidentified signal molecules co-ordinate the activity of the Gac/Rsm cascade in a cell population density-dependent manner.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                June 2014
                19 June 2014
                : 10
                : 6
                : e1004440
                Affiliations
                [1]Department of Microbiology, Immunobiology and Genetics, Max F. Perutz Laboratories, Center of Molecular Biology, University of Vienna, Vienna, Austria
                The University of Texas Health Science Center at Houston, United States of America
                Author notes

                The authors have declared that no competing interests exist.

                Conceived and designed the experiments: ES UB. Performed the experiments: ES. Analyzed the data: ES UB. Contributed reagents/materials/analysis tools: ES UB. Wrote the paper: ES UB.

                Article
                PGENETICS-D-14-00097
                10.1371/journal.pgen.1004440
                4063720
                24945892
                b37069bd-6fae-4153-b8b4-0e96146119a1
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 10 January 2014
                : 30 April 2014
                Page count
                Pages: 14
                Funding
                This work was supported by the Austrian Science Fund (FWF) through the Special Research Program RNA-REG F43, subproject AF4311 (UB) and through a Hertha-Firnberg Research fellowship T448-B20 (ES).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Metabolism
                Carbohydrate Metabolism
                Genetics
                Molecular Genetics
                Microbiology
                Bacteriology
                Bacterial Physiology
                Gram Negative Bacteria
                Medical Microbiology
                Microbial Pathogens
                Bacterial Pathogens
                Microbial Physiology
                Microbial Metabolism

                Genetics
                Genetics

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