Posttranscription Initiation Control of Gene Expression Mediated by Bacterial RNA-Binding Proteins

Babitzke, Paul; Lai, Ying Jung; Renda, Andrew; Romeo, Tony

doi:10.1146/annurev-micro-020518-115907

Cited by 46 publications

(41 citation statements)

References 166 publications

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“…Much of this recent progress has come from studies in Gram‐negative bacteria, especially Escherichia coli and Salmonella enterica (Hör et al , , ). These model bacteria express at least three global RBPs—CsrA, Hfq, and ProQ—that form complexes with hundreds of different sRNAs to facilitate extensive post‐transcriptional control of mRNAs (Olejniczak & Storz, ; Holmqvist & Vogel, ; Kavita et al , ; Babitzke et al , ). The situation is very different with Gram‐positive bacteria: Despite much evidence that sRNAs also play important roles in these organisms (Brantl & Brückner, ; Wagner & Romby, ; Quereda & Cossart, ; Wassarman, ; Desgranges et al , ), many aspects of their sRNA biology seem to differ from Gram‐negative species.…”

Section: Introductionmentioning

confidence: 99%

Grad‐seq in a Gram‐positive bacterium reveals exonucleolytic sRNA activation in competence control

et al. 2020

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RNA-protein interactions are the crucial basis for many steps of bacterial gene expression, including post-transcriptional control by small regulatory RNAs (sRNAs). In stark contrast to recent progress in the analysis of Gram-negative bacteria, knowledge about RNAprotein complexes in Gram-positive species remains scarce. Here, we used the Grad-seq approach to draft a comprehensive landscape of such complexes in Streptococcus pneumoniae, in total determining the sedimentation profiles of~88% of the transcripts and~62% of the proteins of this important human pathogen. Analysis of in-gradient distributions and subsequent tag-based protein capture identified interactions of the exoribonuclease Cbf1/YhaM with sRNAs that control bacterial competence for DNA uptake. Unexpectedly, the nucleolytic activity of Cbf1 stabilizes these sRNAs, thereby promoting their function as repressors of competence. Overall, these results provide the first RNA/protein complexome resource of a Gram-positive species and illustrate how this can be utilized to identify new molecular factors with functions in RNA-based regulation of virulence-relevant pathways.

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Section: Introductionmentioning

confidence: 99%

Grad‐seq in a Gram‐positive bacterium reveals exonucleolytic sRNA activation in competence control

et al. 2020

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“…These studies used random transposon mutagenesis to identify trans-acting factors affecting glycogen biosynthesis and expression of a glgC'-'lacZ translational reporter . At that time, transcript initiation was understood to be a focal point of genetic regulation, while translational regulation and posttranscriptional regulation were limited to a few examples, such as feedback inhibition of ribosomal protein synthesis (discussed in Babitzke et al, 2009Babitzke et al, , 2019Vakulskas et al, 2015).…”

Section: Introduction and Historymentioning

confidence: 99%

Diverse Mechanisms and Circuitry for Global Regulation by the RNA-Binding Protein CsrA

et al. 2020

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The carbon storage regulator (Csr) or repressor of stationary phase metabolites (Rsm) system of Gammaproteobacteria is among the most complex and best-studied posttranscriptional regulatory systems. Based on a small RNA-binding protein, CsrA and homologs, it controls metabolism, physiology, and bacterial lifestyle decisions by regulating gene expression on a vast scale. Binding of CsrA to sequences containing conserved GGA motifs in mRNAs can regulate translation, RNA stability, riboswitch function, and transcript elongation. CsrA governs the expression of dozens of transcription factors and other regulators, further expanding its influence on cellular physiology, and these factors can participate in feedback to the Csr system. Expression of csrA itself is subject to autoregulation via translational inhibition and indirect transcriptional activation. CsrA activity is controlled by small noncoding RNAs (sRNAs), CsrB and CsrC in Escherichia coli, which contain multiple high affinity CsrA binding sites that compete with those of mRNA targets. Transcription of CsrB/C is induced by certain nutrient limitations, cellular stresses, and metabolites, while these RNAs are targeted for degradation by the presence of a preferred carbon source. Consistent with these findings, CsrA tends to activate pathways and processes that are associated with robust growth and repress stationary phase metabolism and stress responses. Regulatory loops between Csr components affect the signaling dynamics of the Csr system. Recently, systems-based approaches have greatly expanded our understanding of the roles played by CsrA, while reinforcing the notion that much remains to be learned about the Csr system.

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“…Specifically, base-pairing sRNAs, such as trans -acting sRNAs, bind to transcripts and modulate their expression by either altering their stability or their ability to be translated [47,49,69]. Alternatively, protein-binding sRNAs can bind to cellular proteins and modify their activity [44,45,48]. Regulation via sRNAs is fast acting and functions as an additional layer in response to environmental signals [43, 70].…”

Section: Discussionmentioning

confidence: 99%

The Intergenic Small Non-Coding RNAittAis Required for Optimal Infectivity and Tissue Tropism inBorrelia burgdorferi

Medina-Pérez

Wager

Troy

et al. 2020

Preprint

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ABSTRACTPost-transcriptional regulation via small regulatory RNAs (sRNAs) has been implicated in diverse regulatory processes in bacteria, including virulence. One class of sRNAs, termed trans-acting sRNAs, can affect the stability and/or the translational efficiency of regulated transcripts. In this study, we utilized a collaborative approach that employed data from infection with the Borrelia burgdorferi Tn library, coupled with Tn-seq, together with borrelial sRNA and total RNA transcriptomes, to identify an intergenic trans-acting sRNA, which we designate here as ittA for infectivity-associated and tissue-tropic sRNA locus A. The genetic inactivation of ittA resulted in a significant attenuation in infectivity, with decreased spirochetal load in ear, heart, skin and joint tissues. In addition, the ittA mutant did not disseminate to peripheral skin sites or heart tissue, suggesting a role for ittA in regulating a tissue-tropic response. RNA-Seq analysis determined that 19 transcripts were differentially expressed in the ittA mutant relative to its genetic parent, including vraA, bba66, ospD and oms28 (bba74). Subsequent proteomic analyses also showed a significant decrease of OspD and Oms28 (BBA74) proteins. To our knowledge this is the first documented intergenic sRNA that alters the infectivity potential of B. burgdorferi.AUTHOR SUMMARYLyme disease is a tick-borne infection mediated by the spirochetal bacterium, Borrelia burgdorferi, that is responsible for greater than 300,000 infections in the United States per year. As such, additional knowledge regarding how this pathogen modulates its regulatory armamentarium is needed to understand how B. burgdorferi establishes and maintains infection. The identification and characterization of small, non-coding RNA molecules in living systems, designated as sRNAs, has recalibrated how we view post-transcriptional regulation. Recently, over 1,000 sRNAs were identified in B. burgdorferi. Despite the identification of these sRNAs, we do not understand how they affect infectivity or B. burgdorferi pathogenesis related outcomes. Here, we characterize the ittA B. burgdorferi sRNA and show that it is essential for optimal infection using murine experimental infection as our readout. We also track the effect of this sRNA on the transcriptional and proteomic profile as the first step in providing mechanistic insight into how this important sRNA mediates its regulatory effect.

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Posttranscription Initiation Control of Gene Expression Mediated by Bacterial RNA-Binding Proteins

Cited by 46 publications

References 166 publications

Grad‐seq in a Gram‐positive bacterium reveals exonucleolytic sRNA activation in competence control

Grad‐seq in a Gram‐positive bacterium reveals exonucleolytic sRNA activation in competence control

Diverse Mechanisms and Circuitry for Global Regulation by the RNA-Binding Protein CsrA

The Intergenic Small Non-Coding RNAittAis Required for Optimal Infectivity and Tissue Tropism inBorrelia burgdorferi

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