BldC delays entry into development to produce a sustained period of vegetative growth in<i>Streptomyces venezuelae</i>

Bush, Matthew J.; Al-Bassam, Mahmoud J.; Chandra, Govind; Findlay, Kim; Buttner, Mark J.

doi:10.1101/194126

Cited by 7 publications

(11 citation statements)

References 44 publications

(71 reference statements)

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“…The four direct BldD‐(c‐di‐GMP) targets ( cdgA , cdgB , cdgC , and cdgE ) are also directly controlled by the response regulator MtrA, which further binds to the promoters of cdgF and rmdB (Som et al ., 2017). Moreover, cdgB is directly repressed by the transcription factor WhiA, while cdgE is directly activated by the MerR‐like regulator BldC (Bush et al ., 2013, Bush et al ., 2019). Such multilayered transcriptional control of c‐di‐GMP synthesis and degradation suggests that levels of this molecule are fine‐tuned in response to disparate signal transduction cascades.…”

Section: Resultsmentioning

confidence: 99%

Specialized and shared functions of diguanylate cyclases and phosphodiesterases in Streptomyces development

Haist

Neumann

Al‐Bassam

et al. 2020

Molecular Microbiology

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The second messenger bis‐3,5‐cyclic di‐guanosine monophosphate (c‐di‐GMP) determines when Streptomyces initiate sporulation. c‐di‐GMP signals are integrated into the genetic differentiation network by the regulator BldD and the sigma factor σWhiG. However, functions of the development‐specific diguanylate cyclases (DGCs) CdgB and CdgC, and the c‐di‐GMP phosphodiesterases (PDEs) RmdA and RmdB, are poorly understood. Here, we provide biochemical evidence that the GGDEF‐EAL domain protein RmdB from S. venezuelae is a monofunctional PDE that hydrolyzes c‐di‐GMP to 5′pGpG. Despite having an equivalent GGDEF‐EAL domain arrangement, RmdA cleaves c‐di‐GMP to GMP and exhibits residual DGC activity. We show that an intact EAL motif is crucial for the in vivo function of both enzymes since strains expressing protein variants with an AAA motif instead of EAL are delayed in development, similar to null mutants. Transcriptome analysis of ∆cdgB, ∆cdgC, ∆rmdA, and ∆rmdB strains revealed that the c‐di‐GMP specified by these enzymes has a global regulatory role, with about 20% of all S. venezuelae genes being differentially expressed in the cdgC mutant. Our data suggest that the major c‐di‐GMP‐controlled targets determining the timing and mode of sporulation are genes involved in cell division and the production of the hydrophobic sheath that covers Streptomyces aerial hyphae and spores.

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Section: Resultsmentioning

confidence: 99%

Specialized and shared functions of diguanylate cyclases and phosphodiesterases in Streptomyces development

Haist

Neumann

Al‐Bassam

et al. 2020

Molecular Microbiology

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Section: Diverse Functions and Modes Of Dna Binding In The Merr Supermentioning

confidence: 99%

“…Phenotypically, BldC acts to delay entry into development to produce a sustained period of vegetative growth, and so bldC mutants initiate development prematurely [27 ]. BldC binds to hundreds of promoter regions and has a global influence on the transcription profile of the cell, exerting positive effects on the activity of some of its target promoters and negative effects on others [27 ]. Bioinformatic analysis suggested [28] and structural studies demonstrated [29 ] that BldC is related to the DNAbinding domain of MerR family transcription factors like MtaN ( Figure 1) [30], consistent with the transcription factor-like behaviour of BldC.…”

Section: Diverse Functions and Modes Of Dna Binding In The Merr Supermentioning

confidence: 99%

“…Thus, in the way that it binds DNA, BldC is more similar to the architectural protein Xis than to classical MerR transcription factors. Nevertheless, BldC has many of the characteristics of a transcription factor, binding almost exclusively to intergenic regions, positively influencing roughly half of its target promoters and negatively influencing the other half [27 ].…”

Section: Diverse Functions and Modes Of Dna Binding In The Merr Supermentioning

confidence: 99%

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When is a transcription factor a NAP?

Dorman

Schumacher

Bush

et al. 2020

Current Opinion in Microbiology

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Proteins that regulate transcription often also play an architectural role in the genome. Thus, it has been difficult to define with precision the distinctions between transcription factors and nucleoid-associated proteins (NAPs). Anachronistic descriptions of NAPs as 'histone-like' implied an organizational function in a bacterial chromatin-like complex. Definitions based on protein abundance, regulatory mechanisms, target gene number, or the features of their DNAbinding sites are insufficient as marks of distinction, and trying to distinguish transcription factors and NAPs based on their ranking within regulatory hierarchies or positions in genecontrol networks is also unsatisfactory. The terms 'transcription factor' and 'NAP' are ad hoc operational definitions with each protein lying along a spectrum of structural and functional features extending from highly specific actors with few gene targets to those with a pervasive influence on the transcriptome. The Streptomyces BldC protein is used to illustrate these issues.

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“…The four direct BldD-(c-di-GMP) targets ( cdgA, cdgB, cdgC and cdgE ) are also directly controlled by the response regulator MtrA, which further binds to the promoters of cdgF and rmdB (24). Moreover, cdgB is directly repressed by the transcription factor WhiA, while cdgE is directly activated by the MerR-like regulator BldC (41, 42). Such multi-layered transcriptional control of c-di-GMP synthesis and degradation suggests that levels of this molecule are fine-tuned in response to disparate signal transduction cascades.…”

Section: Resultsmentioning

confidence: 99%

Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment

Haist

Neumann

Al‐Bassam³

et al. 2020

Preprint

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25Levels of the second messenger bis-3´-5´-cyclic di-guanosinemonophosphate (c-di-GMP) 26 determine when Streptomyces initiate sporulation to survive under adverse conditions. c-di-27 GMP signals are integrated into the genetic differentiation network by the regulator BldD and 28 the sigma factor σ WhiG . However, functions of the development-specific c-di-GMP 29 diguanylate cyclases (DGCs) CdgB and CdgC, and the phosphodiesterases (PDEs) RmdA and 30 RmdB, are poorly understood. Here, we provide biochemical evidence that the GGDEF-EAL 31 domain protein RmdB from S. venezuelae is a monofunctional PDE that hydrolyzes c-di-32 GMP to 5´pGpG. Despite having an equivalent GGDEF-EAL domain arrangement, RmdA 33 cleaves c-di-GMP to GMP and exhibits residual DGC activity. We show that an intact EAL 34 motif is crucial for the in vivo function of both enzymes since strains expressing protein 35 variants with an AAA motif instead of EAL are delayed in development, similar to null 36 mutants. Global transcriptome analysis of ∆cdgB, ∆cdgC, ∆rmdA and ∆rmdB strains revealed 37 that the c-di-GMP specified by these enzymes has a global regulatory role, with about 20 % 38 of all S. venezuelae genes being differentially expressed in the cdgC mutant. Our data suggest 39 that the major c-di-GMP-controlled targets determining the timing and mode of sporulation 40 are genes involved cell division and the production of the hydrophobic sheath that covers 41Streptomyces aerial hyphae and spores. Altogether, this study provides a global view of the c-42 di-GMP-dependent genes that contribute to the hyphae-to-spores transition and sheds light on 43 the shared and specific functions of the key enzymes involved in c-di-GMP metabolism in S. 44 venezuelae. 45 46 245 words 47 48 Importance 49 50Streptomyces are important producers of clinical antibiotics. The ability to synthesize these 51 natural products is connected to their developmental biology, which includes a transition from 52 filamentous cells to spores. The widespread bacterial second messenger c-di-GMP controls 53 this complex switch and is a promising tool to improve antibiotic production. Here, we 54 analyzed the enzymes that make and break c-di-GMP in S. venezuelae by studying the 55 genome-wide transcriptional effects of the DGCs CdgB and CdgC and the PDEs RmdA and 56RmdB. We found that the c-di-GMP specified by these enzymes has a global regulatory role. 57 However, despite shared enzymatic activities, the four c-di-GMP enzymes have specialized 58 inputs into differentiation. Altogether, we demonstrate that altering c-di-GMP levels through 59 the action of selected enzymes yields characteristically distinct transcriptional profiles; this 60 can be an important consideration when modulating c-di-GMP for the purposes of natural 61 product synthesis in Streptomyces. 62 63 143 words 64 65 66 Streptomyces development is controlled by a complex network of Bld and Whi 100 regulators. Strains mutated in bld genes fail to develop aerial hyphae, while deletion of whi 101 genes blocks t...

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BldC delays entry into development to produce a sustained period of vegetative growth inStreptomyces venezuelae

Abstract: 14 not peer-reviewed)

Cited by 7 publications

References 44 publications

Specialized and shared functions of diguanylate cyclases and phosphodiesterases in Streptomyces development

Specialized and shared functions of diguanylate cyclases and phosphodiesterases in Streptomyces development

When is a transcription factor a NAP?

Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment

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