c-di-GMP Arms an Anti-σ to Control Progression of Multicellular Differentiation in Streptomyces

Gallagher, Kelley A.; Schumacher, Maria A.; Bush, Matthew J.; Bibb, Maureen J.; Chandra, Govind; Holmes, Neil A.; Zhang, Wenjie; Henderson, Max; Zhang, Hengshan; Findlay, Kim; Brennan, Richard G.; Buttner, Mark J.

doi:10.1016/j.molcel.2019.11.006

Cited by 66 publications

(101 citation statements)

References 100 publications

(149 reference statements)

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“…The expression of whiI and whiH is directly activated by the sigma factor σ WhiG , whose activity is controlled by the RsiG-(c-di-GMP) anti-sigma factor. Expression of whiI completely depends on whiG , whereas whiH expression is only partially dependent on the sigma factor (11). Thus, the fact that whiI was upregulated in both Δ cdgB and Δ cdgC , reflected the activation of σ WhiG in the two DGC mutants.…”

Section: Resultsmentioning

confidence: 99%

“…whiE expression is controlled by the sporulation-specific BldM-WhiI heterodimer (44). Since whiI is transcribed in an RsiG-(c-di-GMP)-σ WhiG -controlled manner (11), this regulatory circuit is likely responsible for the whiE sensitivity to c-di-GMP.…”

Section: Resultsmentioning

confidence: 99%

“…Through the sporulation-specific regulators WhiI and WhiH, σ WhiG thus controls a large regulon of sporulation genes. Overexpressing either whiG or co-overexpressing whiI and whiH , induces hypersporulation (11), as seen for Δ cdgC .…”

Section: Introductionmentioning

confidence: 82%

“…Strains mutated in bld genes fail to develop aerial hyphae, while deletion of whi genes blocks the transition of aerial hyphae into spores (10). c-di-GMP signals are integrated in the two Streptomyces cell-fate establishing stages and determine (I) the period of vegetative, filamentous growth by binding to the transcriptional regulator, BldD, (6) and (II) initiation of sporulation by controlling the activity of the sporulation-specific sigma factor σ WhiG (11). Binding of c-di-GMP to BldD induces protein dimerization and stimulates BldD-binding to target DNA.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment

Haist

Neumann

Al‐Bassam³

et al. 2020

Preprint

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“…Generally, they produce reproductive aerial hyphae from vegetative mycelia, which differentiate into the exospore chains (Bush, Tschowri, Schlimpert, Flärdh, & Buttner, ; Flärdh & Buttner, ). The sporulation‐specific sigma factor σ WhiG , which is highly similar to FliA, is known to play a key regulatory role in the differentiation of the reproductive aerial hyphae into spores (Chater et al, ; Flärdh, Findlay, & Chater, ; Gallagher et al, ). Thus, the FliA/WhiG‐family sigma factor σ WhiG is dedicated to the expression of developmental genes in the non‐motile filamentous genus Streptomyces , while FliA is mainly utilized for the expression of motility‐related genes in the motile unicellular bacteria such as B. subtilis , E. coli and Salmonella .…”

Section: Introductionmentioning

confidence: 99%

Involvement of three FliA‐family sigma factors in the sporangium formation, spore dormancy and sporangium dehiscence in Actinoplanes missouriensis

Hashiguchi

Tezuka

Ohnishi

2020

Molecular Microbiology

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The rare actinomycete Actinoplanes missouriensis forms sporangia, which open up and release zoospores in response to water. Here, we report a genetic and functional analysis of four FliA‐family sigma factors, FliA1, FliA2, FliA3 and FliA4. Transcription of fliA1, fliA2 and fliA3 was directly activated by the global transcriptional activator TcrA during sporangium formation and dehiscence, while fliA4 was almost always transcribed at low levels. Gene disruption analysis showed that (a) deletion of fliA2 reduced the zoospore swimming speed by half, (b) the fliA1‐fliA2 double‐deletion mutant formed abnormal sporangia in which mutant spores ectopically germinated and (c) deletion of fliA3 induced no phenotypic changes in the wild‐type and mutant strains of fliA1 and/or fliA2. Comparative RNA‐Seq analyses among the wild‐type and gene deletion mutant strains showed probable targets of each FliA‐family sigma factor, indicating that FliA1‐ and FliA2‐dependent promoters are quite similar to each other, while the FliA3‐dependent promoter is somewhat different. Gene complementation experiments also indicated that the FliA1 regulon overlaps with the FliA2 regulon. These results demonstrate that A. missouriensis has developed a complex transcriptional regulatory network involving multiple FliA‐family sigma factors for the accomplishment of its characteristic reproduction process, including sporangium formation, spore dormancy and sporangium dehiscence.

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Streptomycete Spores

Elliot¹,

Flärdh²

2020

Encyclopedia of Life Sciences

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The Gram‐positive Streptomyces bacteria are major inhabitants of soil, and, unusually for bacteria, they have a complex, multicellular life cycle that looks remarkably fungal‐like. Vegetative growth involves the extension of multicellular, branching hyphae, while reproductive growth involves the emergence of nonbranching hyphae into the air, away from the branching vegetative hyphal mass. These aerial hyphae are converted into chains of prespore compartments by coordinated cell division and chromosome segregation. Prespores then mature into thick‐walled spores that have condensed nucleoids, low metabolic activity and are primed for dispersal and survival. Aerial hyphae and spore surfaces are coated with a hydrophobic, proteinaceous fibrous sheath that aids in aerial growth and may help to promote subsequent spore dispersal and interaction with various interfaces. When exposed to appropriate environmental conditions, spores re‐establish metabolic activity, initiate germination and begin the vegetative phase of their life cycle anew. Key Concepts Streptomyces spores are distinctly different from bacterial endospores and may be regarded as a type of exospore. Spores develop from dedicated reproductive structures called aerial hyphae. Streptomyces spores are formed by partitioning long, multigenomic hyphal cells into unigenomic prespore compartments, through developmentally regulated cell division and chromosome segregation events. An outer fibrous sheath, containing the lanthionine peptide SapB, the chaplins and the rodlins, confers surface hydrophobicity to aerial hyphae and spores. A dedicated ‘ Streptomyces spore wall synthesis complex’ directs the development of a thick spore wall that contributes to mature spore quiescence and resilience. Spores have reduced metabolic activity, accumulate trehalose and have condensed nucleoids. Germination involves rehydration, symmetrical swelling and establishment of polar growth, leading to germ tube emergence and vegetative hyphal outgrowth.

show abstract

c-di-GMP Arms an Anti-σ to Control Progression of Multicellular Differentiation in Streptomyces

Cited by 66 publications

References 100 publications

Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment

Specialized and shared functions of diguanylate cyclases and phosphodiesterases inStreptomycesdevelopment

Involvement of three FliA‐family sigma factors in the sporangium formation, spore dormancy and sporangium dehiscence in Actinoplanes missouriensis

Streptomycete Spores

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