A multifaceted small
            <scp>RNA</scp>
            modulates gene expression upon glucose limitation in
            <i>Staphylococcus aureus</i>

Bronesky, Delphine; Desgranges, Emma; Corvaglia, Anna Rita; François, Patrice; Caballero, Carlos J; Prado, Laura; Toledo‐Arana, Alejandro; Lasa, Íñigo; Moreau, Karen; Vandenesch, François; Marzi, Stefano; Romby, Pascale; Caldelari, Isabelle

doi:10.15252/embj.201899363

Cited by 50 publications

(93 citation statements)

References 70 publications

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“…Second, others have shown that rsaD is dependent on Sigma B (Geissmann et al, 2009), the alternative sigma factor responsible for activating the general stress response in S. aureus, as well as playing critical roles in virulence and persistence (Chaturongakul, Raengpradub, Wiedmann, & Boor, 2008;Hecker, Pané-Farré, & Völker, 2007;Mitchell et al, 2013;Novick, 2003;Tuchscherr et al, 2015). How SigB controls rsaD expression, whether by directly binding to the rsaD promoter or through an indirect method, requires further study since there exists a lack of understanding SigB activation in S. aureus compared to related (Bronesky et al, 2019). SrrAB is a regulatory system that influences virulence factor expression, including genes important for biofilm formation and even programmed cell lysis.…”

Section: Rsad Integrates Multiple Signals Into Staphylococcal Regulmentioning

confidence: 99%

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Augagneur

King

Germain-Amiot

et al. 2019

Molecular Microbiology

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In Staphylococcus aureus, the transcription factor CodY modulates the expression of hundreds of genes, including most virulence factors, in response to the availability of key nutrients like GTP and branched‐chain amino acids. Despite numerous studies examining how CodY controls gene expression directly or indirectly, virtually nothing is known about the extent to which CodY exerts its effect through small regulatory RNAs (sRNAs). Herein, we report the first set of sRNAs under the control of CodY. We reveal that staphylococcal sRNA RsaD is overexpressed >20‐fold in a CodY‐deficient strain in three S. aureus clinical isolates and in S. epidermidis. We validated the CodY‐dependent regulation of rsaD and demonstrated that CodY directly represses rsaD expression by binding the promoter. Using a combination of molecular techniques, we show that RsaD posttranscriptionally regulates alsS (acetolactate synthase) mRNA and enzyme levels. We further show that RsaD redirects carbon overflow metabolism, contributing to stationary phase cell death during exposure to weak acid stress. Taken together, our data delineate a role for CodY in controlling sRNA expression in a major human pathogen and indicate that RsaD may integrate nutrient depletion and other signals to mount a response to physiological stress experienced by S. aureus in diverse environments.

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Section: Rsad Integrates Multiple Signals Into Staphylococcal Regulmentioning

confidence: 99%

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Augagneur

King

Germain-Amiot

et al. 2019

Molecular Microbiology

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“…It increases the translation of Sbi immune evasion molecules, and consequently weakens the innate and adaptive immune responses (22,23). In addition to these examples, only a handful of sRNAs have been assessed for functions, including identifying their targets (6,7,(24)(25)(26)(27)(28)(29)(30).…”

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confidence: 99%

Comparative Transcriptomic and Functional Assessments of Linezolid-Responsive Small RNA Genes in Staphylococcus aureus

et al. 2020

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Staphylococcus aureus contains a repertoire of at least 50 and possibly 500 small RNAs (sRNAs). The functions of most sRNAs are not understood, although some are known to respond to environmental changes, including the presence of antibiotics. Here, in an effort to better understand the roles of sRNAs in the context of antibiotic exposure, we took a clinical methicillin-resistant S. aureus (MRSA) isolate and separately deleted eight sRNAs that were significantly upregulated in response to the last-line antibiotic linezolid as revealed by transcriptome sequencing (RNA-seq) comparisons. We also deleted an additional 10 sRNAs that were either highly expressed or previously found to respond to antibiotic exposure. There were no significant changes for any of the 18 mutants in a variety of phenotypic screens, including MIC screens, growth competition assays in the presence of linezolid, biofilm formation, and resistance to whole-blood killing. These data suggest sRNA functional redundancy, because despite their high expression levels upon antibiotic exposure, individual sRNA genes do not affect readily observable bacterial phenotypes. The sRNA transcriptional changes we measured during antibiotic exposure might also reflect sRNA “indifference,” that is, a general stress response not specifically related to sRNA function. These data underscore the need for sensitive assays and new approaches to try and decipher the functions of sRNA genes in S. aureus. IMPORTANCE Bacterial small RNAs (sRNAs) are RNA molecules that can have important regulatory roles across gene expression networks. There is a growing understanding of the scope and potential breadth of impact of sRNAs on global gene expression patterns in Staphylococcus aureus, a major human pathogen. Here, transcriptome comparisons were used to examine the roles of sRNA genes with a potential role in the response of S. aureus to antibiotic exposure. Although no measurable impact on key bacterial phenotypes was observed after deleting each of 18 sRNAs identified by these comparisons, this research is significant because it underscores the subtle modes of action of these sometimes abundant molecules within the bacterium.

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“…In contrast, RosA is a stand-alone sRNA. Interestingly, another stand-alone sRNA in S. aureus , namely RsaI (RsaOG), was also shown to be CcpA-regulated and to interact with the sRNAs RsaG, RsaD and RsaE, the RoxS homologue in S. aureus , 52 . RsaI, like RosA, contains two G-rich regions to bind to RsaG, RsaD and RsaE.…”

Section: Discussionmentioning

confidence: 99%

Novel regulation from novel interactions: Identification of an RNA sponge that controls the levels, processing and efficacy of the RoxS riboregulator of central metabolism inBacillus subtilis

Durand

Callan-Sidat

McKeown

et al. 2019

Preprint

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Small RNAs (sRNAs) are a taxonomically-restricted but transcriptomically-abundant class of post-transcriptional regulators. While potentially of importance, we know the function of few. This is in no small part because we lack global-scale methodology enabling target identification, this being especially acute in species without known RNA meeting point proteins (e.g. Hfq). We apply a combination of psoralen RNA cross-linking and Illumina-sequencing to identify RNA-RNA interacting pairs in vivo in Bacillus subtilis, resolving previously well-described interactants. Although sRNA-sRNA pairings are rare (compared with sRNA/mRNA), we identify a robust example involving the unusually conserved sRNA (RoxS/RsaE) and an unstudied sRNA that we term Regulator of small RNA A (RosA). This interaction is found in independent samples across multiple conditions. Given the possibility of a novel associated regulatory mechanism, and the rarity of well-characterised bacterial sRNA-sRNA interactions, we mechanistically dissect RosA and its interactants. RosA we show to be a sponge RNA, the first to be described in a Gram-positive bacterium. RosA interacts with at least two sRNAs, RoxS and FsrA. Unexpectedly, it acts differently on each. As expected of a sponge RNA, FsrA is sequestered by RosA. The RosA/RoxS interaction is more complex affecting not only the level of RoxS but also its processing and efficacy. Importantly, RosA provides the condition-dependent intermediary between CcpA, the key regulator of carbon metabolism, and RoxS. This not only provides evidence for a novel, and functionally important, regulatory mechanism, but in addition, provides the missing link between transcriptional and post-transcriptional regulation of central metabolism.

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A multifaceted small RNA modulates gene expression upon glucose limitation in Staphylococcus aureus

Cited by 50 publications

References 70 publications

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Analysis of the CodY RNome reveals RsaD as a stress‐responsive riboregulator of overflow metabolism in Staphylococcus aureus

Comparative Transcriptomic and Functional Assessments of Linezolid-Responsive Small RNA Genes in Staphylococcus aureus

Novel regulation from novel interactions: Identification of an RNA sponge that controls the levels, processing and efficacy of the RoxS riboregulator of central metabolism inBacillus subtilis

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