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RNA‐mediated signal perception in pathogenic bacteria

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Bacterial pathogens encounter several different environments during an infection, many of them possibly being detrimental. In order to sense its surroundings and adjust the gene expression accordingly, different regulatory schemes are undertaken. With these, the bacterium appropriately can differentiate between various environmental cues to express the correct virulence factor at the appropriate time and place. An attractive regulator device is RNA, which has an outstanding ability to alter its structure in response to external stimuli, such as metabolite concentration or alterations in temperature, to control its downstream gene expression. This review will describe the function of riboswitches and thermometers, with a particular emphasis on regulatory RNAs being important for bacterial pathogenicity. WIREs RNA 2017, 8:e1429. doi: 10.1002/wrna.1429 This article is categorized under: RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems Translation > Translation Regulation Regulatory RNAs/RNAi/Riboswitches > Riboswitches
Diversity of riboswitch expression platforms. Expression of the genes downstream of the riboswitches can either be repressed (‘OFF’) or activated (‘ON’) by binding of the ligand. (a) The flavin mononucleotide (FMN) riboswitch from Bacillus subtilis forms the termination hairpin in the presence of FMN. The antiterminator hairpin, which forms in the absence of FMN, is shown in orange. (b) The adenine riboswitch upstream of ydhL gene in B. subtilis activates transcription in the presence of adenine by the rearrangement of the terminator hairpin. (c) The Mg2+ riboswitch from Salmonella enterica serovar Typhimurium sequesters Rho utilization site at low Mg2+ concentration. At high Mg2+ concentration, the Rho factor can bind the mRNA and cause termination of transcription. (d) The TPP riboswitch from Escherichia coli blocks access to the Shine–Dalgarno (SD) site by base pairing with anti‐SD site at high TPP concentration. At low TPP levels, the anti‐SD site is sequestered, allowing binding of the ribosome (yellow) to the SD site. (e) The SAM‐II riboswitch sequesters the SD site within a pseudoknot structure upon ligand binding. (f) The lysC riboswitch from E. coli inhibits expression of the gene by two mechanisms: blocking access to the SD site and exposing the recognition site of RNAse E. (g) The GlmS ribozyme binds glucosamine‐6‐phosphate (GlcN6P) and uses it as a cofactor to cleave the 5′ UTR. The downstream cleavage fragment bears 5′ OH group, which recruits RNase J, leading to the mRNA degradation. (h) The c‐di‐GMP‐I riboswitch in C. difficile regulates the splicing of group I self‐splicing ribozyme, which is located in the 5′ UTR of a gene and regulates its translation. Before the self‐splicing occurs, the start codon UUG is sequestered inside the hairpin. Additionally, the SD site is separated from the open reading frame (ORF) by the ribozyme sequence. These properties do not allow translation of the prespicing mRNA. In the absence of c‐di‐GMP, self‐splicing is initiated by Guanosine triphosphate (GTP) attack at the site located near the start codon and leads to the mRNA not containing the proper SD site. Binding of c‐di‐GMP by the riboswitch aptamer causes rearrangement of the ribozyme structure. In this case, GTP attacks another site located adjacent to the SD site sequence. Self‐splicing in the presence of c‐di‐GMP forms mRNA containing the properly located SD site, which binds the ribosome and is efficiently translated.
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Different architectures of RNA thermometers. (a) The structure of the repression of heat‐shock gene expression (ROSE) thermosensor from Bradyrhizobium japonicum. (b) The structure of FourU RNA thermometer regulating lcrF gene in Yersinia pseudotuberculosis. (c) The ‘riboswitch thermostat’ from Vibrio vulnificus represents an adenine ON riboswitch, which can assume two alternative conformations A and B in the absence of adenine. The equilibrium between these conformations is shifted toward conformation A at 37°C, and toward conformation B at 10°C. Only conformation A can bind adenine and activate translation by making the Shine–Dalgarno (SD) site accessible for the ribosome (yellow). (d) The structure and the mechanism of action of PrfA thermosensor in L. monocytogenes. Upon increasing the temperature from 25 to 37°C, the thermosensing hairpin melts, and the ribosome (yellow) can bind the SD site and initiate translation. The prematurely terminated S‐adenosylmethionine (SAM) riboswitch can bind the thermosensing hairpin and block binding of the ribosome.
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Riboswitches in virulence. ‘ON’ riboswitches are shown as green boxes, ‘OFF’ riboswitches are shown as red boxes. (a) c‐di‐AMP riboswitch in Streptomyces coelicolor inhibits expression of rpfA gene at high c‐di‐AMP levels. The RpfA protein participates in activation of dormant cells. (b) c‐di‐GMP riboswitch in Vibrio cholerae activates expression of gbpA gene at high c‐di‐GMP concentration. GbpA mediates colonization of intestines during infection and chitin surfaces in aquatic environment. (c) In Bacillus thuringiensis, c‐di‐GMP riboswitch activates expression of the cap gene at high c‐di‐GMP levels. Cap protein mediates collagen adhesion during infection. (d) In Clostridium difficile, c‐di‐GMP‐sensing riboswitch activates gene pilA1, which leads to type IV pili synthesis, causing aggregation and formation of biofilms. Another c‐di‐GMP riboswitch inhibits expression of genes for flagella biosynthesis, causing decreased motility. (e) c‐di‐GMP riboswitch upregulates expression of CD2831, a putative adhesine. Another c‐di‐GMP riboswitch inhibits expression of the metalloprotease ZmpI, which can cleave CD2831 from the cell surface. (f) In Listeria monocytogenes, a B12 riboswitch regulates expression of antisense RNA aspocR. This antisense RNA downregulates expression of pocR gene at low, but not at high B12 concentration. pocR encodes a transcriptional regulator activating genes necessary for propanediol utilization. (g) In L. monocytogenes, a B12 riboswitch inhibits expression of a small RNA Rli55 at high B12 concentration. Rli55 can sequester an antiterminator protein EutV. In the absence of EutV, transcription of eut genes encoding enzymes for ethanolamine utilization is prematurely terminated. EutV is phosphorylated in the presence of ethanolamine and, without sequestering by Rli55, binds to mRNAs of eut genes and inhibits premature termination of transcription.
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RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems
Translation > Translation Regulation
Regulatory RNAs/RNAi/Riboswitches > Riboswitches

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