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AdpA Positively Regulates Morphological Differentiation and Chloramphenicol Biosynthesis in Streptomyces venezuelae.

ABSTRACT: In members of genus Streptomyces, AdpA is a master transcriptional regulator that controls the expression of hundreds of genes involved in morphological differentiation, secondary metabolite biosynthesis, chromosome replication, etc. However, the function of AdpASv, an AdpA ortholog of Streptomyces venezuelae, is unknown. This bacterial species is a natural producer of chloramphenicol and has recently become a model organism for studies on Streptomyces. Here, we demonstrate that AdpASv is essential for differentiation and antibiotic biosynthesis in S. venezuelae and provide evidence suggesting that AdpASv positively regulates its own gene expression. We speculate that the different modes of AdpA-dependent transcriptional autoregulation observed in S. venezuelae and other Streptomyces species reflect the arrangement of AdpA binding sites in relation to the transcription start site. Lastly, we present preliminary data suggesting that AdpA may undergo a proteolytic processing and we speculate that this may potentially constitute a novel regulatory mechanism controlling cellular abundance of AdpA in Streptomyces. IMPORTANCE Streptomyces are well-known producers of valuable secondary metabolites which include a large variety of antibiotics and important model organisms for developmental studies in multicellular bacteria. The conserved transcriptional regulator AdpA of Streptomyces exerts a pleiotropic effect on cellular processes, including the morphological differentiation and biosynthesis of secondary metabolites. Despite extensive studies, the function of AdpA in these processes remains elusive. This work provides insights into the role of a yet unstudied AdpA ortholog of Streptomyces venezuelae, now considered a novel model organism. We found that AdpA plays essential role in morphological differentiation and biosynthesis of chloramphenicol, a broad-spectrum antibiotic. We also propose that AdpA may undergo a proteolytic processing that presumably constitutes a novel mechanism regulating cellular abundance of this master regulator.

SUBMITTER: Plachetka M

PROVIDER: S-EPMC8653842 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The pleiotropic transcriptional regulator AdpA positively controls morphological differentiation and regulates secondary metabolism in most Streptomyces species. Streptomyces xiamenensis 318 has a linear chromosome 5.96 Mb in size. How AdpA affects secondary metabolism and morphological differentiation in such a naturally minimized genomic background is unknown. Here, we demonstrated that AdpA Sx , an AdpA orthologue in S. xiamenensis, negatively regulates cell growth and sporulation and bidirectionally regulates the biosynthesis of xiamenmycin and polycyclic tetramate macrolactams (PTMs) in S. xiamenensis 318. Overexpression of the adpASx gene in S. xiamenensis 318 had negative effects on morphological differentiation and resulted in reduced transcription of putative ssgA, ftsZ, ftsH, amfC, whiB, wblA1, wblA2, wblE, and a gene encoding sporulation-associated protein (sxim_29740), whereas the transcription of putative bldD and bldA genes was upregulated. Overexpression of adpASx led to significantly enhanced production of xiamenmycin but had detrimental effects on the production of PTMs. As expected, the transcriptional level of the xim gene cluster was upregulated, whereas the PTM gene cluster was downregulated. Moreover, AdpA Sx negatively regulated the transcription of its own gene. Electrophoretic mobility shift assays revealed that AdpA Sx can bind the promoter regions of structural genes of both the xim and PTM gene clusters as well as to the promoter regions of genes potentially involved in the cell growth and differentiation of S. xiamenensis 318. We report that an AdpA homologue has negative effects on morphological differentiation in S. xiamenensis 318, a finding confirmed when AdpA Sx was introduced into the heterologous host Streptomyces lividans TK24.IMPORTANCE AdpA is a key regulator of secondary metabolism and morphological differentiation in Streptomyces species. However, AdpA had not been reported to negatively regulate morphological differentiation. Here, we characterized the regulatory role of AdpA Sx in Streptomyces xiamenensis 318, which has a naturally streamlined genome. In this strain, AdpA Sx negatively regulated cell growth and morphological differentiation by directly controlling genes associated with these functions. AdpA Sx also bidirectionally controlled the biosynthesis of xiamenmycin and PTMs by directly regulating their gene clusters rather than through other regulators. Our findings provide additional evidence for the versatility of AdpA in regulating morphological differentiation and secondary metabolism in Streptomyces.

Project description:The transcription factor AdpA is a key regulator controlling both secondary metabolism and morphological differentiation in Streptomyces. Due to its critical functions, its expression undergoes multilevel regulations at transcriptional, posttranscriptional, and translational levels, yet no posttranslational regulation has been reported. Sulfane sulfur, such as hydro polysulfide (HSnH, n ≥ 2) and organic polysulfide (RSnH, n ≥ 2), is common inside microorganisms, but its physiological functions are largely unclear. Here, we discovered that sulfane sulfur posttranslationally modifies AdpA in Streptomyces coelicolor via specifically reacting with Cys62 of AdpA to form a persulfide (Cys62-SSH). This modification decreases the affinity of AdpA to its self-promoter PadpA, allowing increased expression of adpA, further promoting the expression of its target genes actII-4 and wblA. ActII-4 activates actinorhodin biosynthesis, and WblA regulates morphological development. Bioinformatics analyses indicated that AdpA-Cys62 is highly conserved in Streptomyces, suggesting the prevalence of such modification in this genus. Thus, our study unveils a new type of regulation on the AdpA activity and sheds a light on how sulfane sulfur stimulates the production of antibiotics in Streptomyces. IMPORTANCE Streptomyces species produce a myriad of natural products with (potential) clinical applications. While the database of biosynthetic gene clusters is quickly expanding, their regulation mechanisms are rarely known. Sulfane sulfur species are commonly present in microorganisms with unclear functions. Here, we discovered that sulfane sulfur increases actinorhodin (ACT) production in S. coelicolor. The underlying mechanism is that sulfane sulfur specifically reacts with AdpA, a global transcription factor controlling both ACT gene cluster and morphological differentiation-related genes, to form sulfhydrated AdpA. This modification changes the dynamics of AdpA-controlled gene networks and leads to high expression of ACT biosynthetic genes. Given the wide prevalence of AdpA and sulfane sulfur in Streptomyces, this mechanism may represent a common regulating pattern of all AdpA-controlled biosynthetic pathways. Thus, this finding provides a new strategy for mining and activating valuable biosynthetic gene clusters.

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AdpA Positively Regulates Morphological Differentiation and Chloramphenicol Biosynthesis in Streptomyces venezuelae.

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