tmRNA Decreases the Bactericidal Activity of Aminoglycosides and the Susceptibility to Inhibitors of Cell Wall Synthesis

Luidalepp, Hannes; Hallier, Marc; Felden, Brice; Tenson, Tanel

doi:10.4161/rna.2.2.2020

Cited by 38 publications

(43 citation statements)

References 28 publications

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“…Trans-translation also impacts the activity of antibacterial drugs that inhibit cell wall synthesis, probably because these drugs induce an overall stress to the bacteria that will be suppressed more efficiently when trans-translation is active. 80 Altogether, these data suggest that either tmRNA, SmpB or the 'tmRNA-SmpB' complex, all structures known at the atomic levels, are promising targets for developing novel antibiotics. Molecules that could bind tmRNA, SmpB or both might interfere with their loading onto the ribosomes to rescue, potentiating the action of the existing drugs and allowing decreasing their active concentrations to limit their side effects.…”

Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 98%

SmpB as the handyman of tmRNA during trans-translation

Felden¹,

Gillet²

2011

RNA Biology

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Section: ©2 0 1 1 L a N D E S B I O S C I E N C E D O N O T D I S Tmentioning

confidence: 98%

SmpB as the handyman of tmRNA during trans-translation

Felden¹,

Gillet²

2011

RNA Biology

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“…Although SsrA is dispensable for the growth of E. coli, SsrA-deficient E. coli cells show several phenotypes including growth defect at extremely high temperature (Komine et al, 1994), lowered level in phage propagation (Withey and Friedman, 1999;Ranquet et al, 2001), delayed induction of the lac operon (Abo et al, 2000), increased sensitivity to several antibiotics (Abo et al, 2002;Luidalepp et al, 2005) and growth inhibition under amino-acid starvation (Li et al, 2008). It is noteworthy that all of these phenotypes could be recovered by SsrA DD ,…”

Section: Introductionmentioning

confidence: 99%

trans-translation-mediated tight regulation of the expression of the alternative ribosome-rescue factor ArfA in Escherichia coli

et al. 2011

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Ribosomes translating mRNA without an in-frame stop codon (non-stop mRNA) stall at its 3' end. In eubacteria, such ribosomes are rescued by SsrA-mediated trans-translation. Recently, we have shown that Escherichia coli ArfA (formerly YhdL) also rescues stalled ribosomes by a mechanism distinct from that of transtranslation. Synthetic lethality phenotype of ssrA arfA double mutants suggests that accumulation of stalled ribosomes is deleterious to E. coli cells. In this report, we show that the expression of ArfA is tightly regulated by the system involving trans-translation. Both premature transcription termination and specific cleavage by RNase III were programmed at the specific sites within the arfA open reading frame (ORF) and produced arfA non-stop mRNA. C-terminally truncated ArfA protein synthesized from arfA non-stop mRNA was tagged through SsrA-mediated trans-translation and degraded in wild type cell. In the absence of SsrA, however, C-terminally truncated ArfA escaped from degradation and had a function to rescue stalled ribosomes. Full-length ArfA produced only when arfA mRNA escapes from both premature transcription termination and RNase III cleavage was unstable. From these results, we illustrate a regulatory model in which ArfA is expressed only when it is needed, namely, when the ribosome rescue activity of trans-translation system is insufficient to support cell viability. This sophisticated regulatory mechanism suggests that the ArfA-mediated ribosome rescue is a backup system for trans-translation.

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“…The most common and effective system for rescuing stalled ribosomes in bacteria consists of transfer-messenger RNA (tmRNA) and its protein partner, SmpB. Genetic deletion of tmRNA is lethal in some species (Huang et al 2000;Ramadoss et al 2013), inhibits pathogenesis in others (Thibonnier et al 2008), and conveys susceptibility to antibiotics and stresses (Muto et al 2000;Luidalepp et al 2005;Thibonnier et al 2008). In a subset of bacteria, there are also redundant mechanisms for releasing stalled ribosomes, including the alternative release factors ArfA, found in β-and γ-proteobacteria (Chadani et al 2010), and ArfB (YaeJ), found in many Gram-negative bacteria (Handa et al 2010;Chadani et al 2011).…”

Section: Introductionmentioning

confidence: 99%

Rejection of tmRNA·SmpB after GTP hydrolysis by EF-Tu on ribosomes stalled on intact mRNA

Kurita

Miller

Muto

et al. 2014

RNA

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Messenger RNAs lacking a stop codon trap ribosomes at their 3 ′ ends, depleting the pool of ribosomes available for protein synthesis. In bacteria, a remarkable quality control system rescues and recycles stalled ribosomes in a process known as transtranslation. Acting as a tRNA, transfer-messenger RNA (tmRNA) is aminoacylated, delivered by EF-Tu to the ribosomal A site, and accepts the nascent polypeptide. Translation then resumes on a reading frame within tmRNA, encoding a short peptide tag that targets the nascent peptide for degradation by proteases. One unsolved issue in trans-translation is how tmRNA and its protein partner SmpB preferentially recognize stalled ribosomes and not actively translating ones. Here, we examine the effect of the length of the 3 ′ extension of mRNA on each step of trans-translation by pre-steady-state kinetic methods and fluorescence polarization binding assays. Unexpectedly, EF-Tu activation and GTP hydrolysis occur rapidly regardless of the length of the mRNA, although the peptidyl transfer to tmRNA decreases as the mRNA 3 ′ extension increases and the tmRNA·SmpB binds less tightly to the ribosome with an mRNA having a long 3 ′ extension. From these results, we conclude that the tmRNA·SmpB complex dissociates during accommodation due to competition between the downstream mRNA and the C-terminal tail for the mRNA channel. Rejection of the tmRNA·SmpB complex during accommodation is reminiscent of the rejection of near-cognate tRNA from the ribosome in canonical translation.

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tmRNA Decreases the Bactericidal Activity of Aminoglycosides and the Susceptibility to Inhibitors of Cell Wall Synthesis

Cited by 38 publications

References 28 publications

SmpB as the handyman of tmRNA during trans-translation

SmpB as the handyman of tmRNA during trans-translation

trans-translation-mediated tight regulation of the expression of the alternative ribosome-rescue factor ArfA in Escherichia coli

Rejection of tmRNA·SmpB after GTP hydrolysis by EF-Tu on ribosomes stalled on intact mRNA

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