SigR, a hub of multilayered regulation of redox and antibiotic stress responses

Park, Joo-Hong; Lee, Juhyung; Roe, Jung‐Hye

doi:10.1111/mmi.14341

Cited by 15 publications

(21 citation statements)

References 74 publications

(146 reference statements)

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“…To better understand how evolution has shaped the regulon of this ECF σ to enable survival in these different niches, we examined which genes were putatively regulated by this ECF σ in the six major actinobacterial orders. SigH/SigR was predicted to regulate 22 to 61 genes, consistent with previous reports (Park, Lee, and Roe 2019;Sharp et al 2016). We identified a core regulon consisting of 6 genes (iscA, trxB, clpC, SCO3296, rbpA, and sigH/R) which were significantly regulated in all 6 orders and an additional 18 genes predicted to be regulated in 4-5 orders.…”

Section: Ecf σ Regulons Are Accurately Predictedsupporting

confidence: 90%

Rewiring the specificity of extra-cytoplasmic function sigma factors

Todor

Osadnik

Campbell

et al. 2020

Preprint

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Bacterial genomes are being sequenced at an exponentially increasing rate, but our inability to decipher their transcriptional wiring limits our ability to derive new biology from these sequences. De novo determination of regulatory interactions requires accurate prediction of regulators' DNA binding and precise determination of biologically significant binding sites. Here, we address these challenges by solving the DNA-specificity code of extra-cytoplasmic function sigma factors (ECF σ s), a major family of bacterial regulators, and determining their regulons.We generated an aligned collection of ECF σ s and their promoters by leveraging the autoregulatory nature of ECF σ s as a means of promoter discovery and analyzed it to identify and characterize the conserved amino acid -nucleotide interactions that determine promoter specificity. This enabled de novo prediction of ECF σ specificity, which we combined with a statistically rigorous phylogenetic foot-printing pipeline based on precomputed orthologs to predict the direct targets of ~67% of ECF σ s. This global survey indicated that ECF σ s play varied roles: some are global regulators controlling many genes throughout the genome that are important under many conditions, while others are local regulators, controlling few closely linked genes in response to specific stimuli. This analysis reveals important organizing principles of bacterial gene regulation and presents a conceptual and computational framework for deciphering gene regulatory networks.

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Section: Ecf σ Regulons Are Accurately Predictedsupporting

confidence: 90%

Rewiring the specificity of extra-cytoplasmic function sigma factors

Todor

Osadnik

Campbell

et al. 2020

Preprint

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“…The functions of those genes are predicted to modify, modulate, or protect translational machinery against antibiotics, supporting the idea that WblC is involved in resuming translation during translational stress mediated by antibiotics. Additionally, it suggests that 19 transcriptional regulators, including WblC itself (11), SigR redox-and antibiotic-responsive sigma factor (27), and NdgR involved in leucine biosynthesis (28), play roles in resolving oxidative stress and adjusting metabolic pathways generated by translation-targeting antibiotics. Cumulatively, these findings imply that WblC-activated genes are involved in a protective response to translation-interrupting antibiotics to maintain viability, which could be an intrinsic resistance mechanism to translation-targeting antibiotics.…”

Section: Category (No Of Genes) Amentioning

confidence: 99%

The WblC/WhiB7 Transcription Factor Controls Intrinsic Resistance to Translation-Targeting Antibiotics by Altering Ribosome Composition

Lee

Yoo

Kim

et al. 2020

mBio

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Bacteria that encounter antibiotics can efficiently change their physiology to develop resistance. This intrinsic antibiotic resistance is mediated by multiple pathways, including a regulatory system(s) that activates specific genes. In some Streptomyces and Mycobacterium spp., the WblC/WhiB7 transcription factor is required for intrinsic resistance to translation-targeting antibiotics. Wide conservation of WblC/WhiB7 within Actinobacteria indicates a critical role of WblC/WhiB7 in developing resistance to such antibiotics. Here, we identified 312 WblC target genes in Streptomyces coelicolor, a model antibiotic-producing bacterium, using a combined analysis of RNA sequencing and chromatin immunoprecipitation sequencing. Interestingly, WblC controls many genes involved in translation, in addition to previously identified antibiotic resistance genes. Moreover, WblC promotes translation rate during antibiotic stress by altering the ribosome-associated protein composition. Our genome-wide analyses highlight a previously unappreciated antibiotic resistance mechanism that modifies ribosome composition and maintains the translation rate in the presence of sub-MIC levels of antibiotics. IMPORTANCE The emergence of antibiotic-resistant bacteria is one of the top threats in human health. Therefore, we need to understand how bacteria acquire resistance to antibiotics and continue growth even in the presence of antibiotics. Streptomyces coelicolor, an antibiotic-producing soil bacterium, intrinsically develops resistance to translation-targeting antibiotics. Intrinsic resistance is controlled by the WblC/WhiB7 transcription factor that is highly conserved within Actinobacteria, including Mycobacterium tuberculosis. Here, identification of the WblC/WhiB7 regulon revealed that WblC/WhiB7 controls ribosome maintenance genes and promotes translation in the presence of antibiotics by altering the composition of ribosome-associated proteins. Also, the WblC-mediated ribosomal alteration is indeed required for resistance to translation-targeting antibiotics. This suggests that inactivation of the WblC/WhiB7 regulon could be a potential target to treat antibiotic-resistant mycobacteria.

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“…In the case of prototypical ECFs, the interaction between the two proteins is mediated by specific binding of the ECF by the anti‐σ domain of the anti‐σ factor (see reviews by Donohue, ; Ho and Ellermeier, ; Park and Roe, in this issue for examples) (Fig. C).…”

Section: Ecfs With Regulator Extensions: the One‐component Systems Ofmentioning

confidence: 99%

ECF σ factors with regulatory extensions: the one‐component systems of the σ universe

Pinto

Liu

Mascher

2019

Molecular Microbiology

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The σ subunit of the bacterial RNA polymerase determines promoter specificity. The extracytoplasmic function σ factors (ECFs) represent the most abundant and diverse group of alternative σ factors and are present in the vast majority of bacterial genomes. Typically, ECFs are regulated by anti-σ factors that sequester their cognate ECFs, thereby preventing their interaction with the RNA polymerase. Beyond these ECF paradigms, a number of distinct modes of regulation have been proposed and experimentally investigated. Regulatory extensions represent one such alternative mechanism of ECF regulation that can be found in 18 phylogenetically distinct ECF groups. Here, the σ factors contain additional domains that are fused to the ECF core domains and are involved in stimulus perception and modulation of σ factor activity. We will summarize the current state of knowledge on regulating ECF activity by C-terminal extensions. We will also discuss newly identified ECF groups containing either N-or C-terminal extensions and propose possible mechanisms by which these extensions have been generated and affect ECF σ factor activity. Based on their modular architecture and the resulting physical connection between stimulus perception and transcriptional output, these ECFs are analogous to one-component systems, the primary mechanism of bacterial signal transduction. contributed equally to the writing of this review.

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SigR, a hub of multilayered regulation of redox and antibiotic stress responses

Cited by 15 publications

References 74 publications

Rewiring the specificity of extra-cytoplasmic function sigma factors

Rewiring the specificity of extra-cytoplasmic function sigma factors

The WblC/WhiB7 Transcription Factor Controls Intrinsic Resistance to Translation-Targeting Antibiotics by Altering Ribosome Composition

ECF σ factors with regulatory extensions: the one‐component systems of the σ universe

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