Bifunctional transfer-messenger RNA

Keiler, Kenneth C.; Ramadoss, Nitya S.

doi:10.1016/j.biochi.2011.05.029

Cited by 25 publications

(20 citation statements)

References 65 publications

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“…Computational sRNA search in A. pleuropneumoniae www.rnajournal.org 1375 (Evans et al 2006), and Arrc23 is a tmRNA, with dual tRNAlike and mRNA properties, which plays a central role in the process of recycling ribosomes stalled in aberrant mRNAs (Keiler and Ramadoss 2011). Both RNAseP and tmRNA use protein cofactors, which are also present in the A. pleuropneumoniae genome.…”

Section: Housekeeping Regulatory Rnasmentioning

confidence: 99%

A computational strategy for the search of regulatory small RNAs in Actinobacillus pleuropneumoniae

Rossi

Bossé

et al. 2016

RNA

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Bacterial regulatory small RNAs (sRNAs) play important roles in gene regulation and are frequently connected to the expression of virulence factors in diverse bacteria. Only a few sRNAs have been described for Pasteurellaceae pathogens and no in-depth analysis of sRNAs has been described for Actinobacillus pleuropneumoniae, the causative agent of porcine pleuropneumonia, responsible for considerable losses in the swine industry. To search for sRNAs in A. pleuropneumoniae, we developed a strategy for the computational analysis of the bacterial genome by using four algorithms with different approaches, followed by experimental validation. The coding strand and expression of 17 out of 23 RNA candidates were confirmed by Northern blotting, RT-PCR, and RNA sequencing. Among them, two are likely riboswitches, three are housekeeping regulatory RNAs, two are the widely studied GcvB and 6S sRNAs, and 10 are putative novel trans-acting sRNAs, never before described for any bacteria. The latter group has several potential mRNA targets, many of which are involved with virulence, stress resistance, or metabolism, and connect the sRNAs in a complex gene regulatory network. The sRNAs identified are well conserved among the Pasteurellaceae that are evolutionarily closer to A. pleuropneumoniae and/or share the same host. Our results show that the combination of newly developed computational programs can be successfully utilized for the discovery of novel sRNAs and indicate an intricate system of gene regulation through sRNAs in A. pleuropneumoniae and in other Pasteurellaceae, thus providing clues for novel aspects of virulence that will be explored in further studies.

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Section: Housekeeping Regulatory Rnasmentioning

confidence: 99%

A computational strategy for the search of regulatory small RNAs in Actinobacillus pleuropneumoniae

Rossi

Bossé

et al. 2016

RNA

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“…The purpose of trans-translation is to remove nonstop translation complexes, i.e., translation reactions in which the ribosome has reached the 3′ end of the mRNA without terminating at a stop codon (4)(5)(6). These complexes are prevalent in bacteria because bacterial ribosomes do not require any information from the 3′ end of the mRNA to initiate translation, and bacteria lack most of the mechanisms for mRNA proofreading found in eukaryotes (7).…”

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confidence: 99%

Small molecule inhibitors of trans -translation have broad-spectrum antibiotic activity

Ramadoss

Alumasa

Cheng

et al. 2013

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

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The trans-translation pathway for protein tagging and ribosome release plays a critical role for viability and virulence in a wide range of pathogens but is not found in animals. To explore the use of trans-translation as a target for antibiotic development, a highthroughput screen and secondary screening assays were used to identify small molecule inhibitors of the pathway. Compounds that inhibited protein tagging and proteolysis of tagged proteins were recovered from the screen. One of the most active compounds, KKL-35, inhibited the trans-translation tagging reaction with an IC 50 = 0.9 μM. KKL-35 and other compounds identified in the screen exhibited broad-spectrum antibiotic activity, validating trans-translation as a target for drug development. This unique target could play a key role in combating strains of pathogenic bacteria that are resistant to existing antibiotics.antibiotic target | tmRNA | non-stop translation T he increasing prevalence of antibiotic-resistant bacterial pathogens has spurred a search for new pathways that can be targeted for antibiotic development (1, 2). One pathway that has not been exploited is the trans-translation pathway, which resolves nonstop translation complexes. The components of trans-translation have been identified in every sequenced bacterial genome, and mutations in these components affect viability or virulence in a wide range of bacteria (3, 4), suggesting that inhibitors of trans-translation might be effective broad-spectrum antibiotics. In addition, the trans-translation pathway is not found in animals, so specific inhibitors are expected to have few side effects on the host.The purpose of trans-translation is to remove nonstop translation complexes, i.e., translation reactions in which the ribosome has reached the 3′ end of the mRNA without terminating at a stop codon (4-6). These complexes are prevalent in bacteria because bacterial ribosomes do not require any information from the 3′ end of the mRNA to initiate translation, and bacteria lack most of the mechanisms for mRNA proofreading found in eukaryotes (7). Because hydrolysis of peptidyl-tRNA by release factors requires a stop codon in the A site, normal translation termination cannot occur when the ribosome reads to the 3′ end of the mRNA and there is no in-frame stop codon. Transtranslation resolves nonstop translation complexes using a ribonucleoprotein complex containing transfer-messenger RNA (tmRNA) and the small protein SmpB (4-6). tmRNA-SmpB recognizes nonstop translation complexes and enters the ribosomal A site mimicking a tRNA (8). The nascent polypeptide is transferred to tmRNA, and a specialized reading frame within tmRNA is inserted into the mRNA channel (4-6). Translation resumes using this sequence as a message and terminates at a stop codon at the end of the reading frame, releasing the ribosome and a tagged protein (4-6). The tag sequence is recognized by proteases, and the tagged protein is rapidly degraded (9-12). The net reaction of trans-translation is the removal of all components o...

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“…Bacterial gene expression is frequently regulated at the level of transcription. A number of recent reports have suggested that the tmRNA-SmpB system plays a regulatory role through regulatory factors (57). These factors might include transcriptional activators and repressors (20,29,56,(58)(59)(60).…”

Section: Discussionmentioning

confidence: 99%

The Transfer-Messenger RNA-Small Protein B System Plays a Role in Avian Pathogenic Escherichia coli Pathogenicity

Huan

et al. 2013

J Bacteriol

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bExtraintestinal pathogenic Escherichia coli (ExPEC) is capable of colonizing outside of the intestinal tract and evolving into a systemic infection. Avian pathogenic E. coli (APEC) is a member of the ExPEC group and causes avian colibacillosis. TransfermRNA-small protein B (tmRNA-SmpB)-mediated trans-translation is a bacterial translational control system that directs the modification and degradation of proteins, the biosynthesis of which has stalled or has been interrupted, facilitating the rescue of ribosomes stalled at the 3= ends of defective mRNAs that lack a stop codon. We found that disruption of one, or both, of the smpB or ssrA genes significantly decreased the virulence of the APEC strain E058, as assessed by chicken infection assays. Furthermore, the mutants were obviously attenuated in colonization and persistence assays. The results of quantitative real-time reverse transcription-PCR analysis indicated that the transcription levels of the transcriptional regulation gene rfaH and the virulence genes kpsM, chuA, and iss were significantly decreased compared to those of the wild-type strain. Macrophage infection assays showed that the mutant strains reduced the replication and/or survival ability in the macrophage HD11 cell line compared to that of the parent strain, E058. However, no significant differences were observed in ingestion by macrophages and in chicken serum resistance between the mutant and the wild-type strains. These data indicate that the tmRNA-SmpB system is important in the pathogenesis of APEC O2 strain E058.

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Bifunctional transfer-messenger RNA

Cited by 25 publications

References 65 publications

A computational strategy for the search of regulatory small RNAs in Actinobacillus pleuropneumoniae

A computational strategy for the search of regulatory small RNAs in Actinobacillus pleuropneumoniae

Small molecule inhibitors of trans -translation have broad-spectrum antibiotic activity

The Transfer-Messenger RNA-Small Protein B System Plays a Role in Avian Pathogenic Escherichia coli Pathogenicity

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