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Evidence of a role for CutRS and actinorhodin in the secretion stress response in Streptomyces coelicolor M145

ABSTRACT: CutRS was the first two-component system to be identified in Streptomyces species and is highly conserved in this genus. It was reported >25 years ago that deletion of cutRS increases the production of the antibiotic actinorhodin in Streptomyces coelicolor but despite this early work the function of CutRS has remained enigmatic until now. Here we show that deletion of cutRS upregulates the production of the actinorhodin biosynthetic enzymes up to 260-fold in the cutRS mutant, explaining the increase in actinorhodin production. However, while ChIP-seq identified 86 CutR binding sites in S. coelicolor none of these are in the actinorhodin BGC, so the effect is indirect. The directly regulated CutR targets identified in this study are implicated in extracellular protein folding, including two of the four highly conserved the HtrA-family foldases, HtrA3 and HtrB and a putative VKOR enzyme which is predicted to recycle DsbA following its catalysis of disulphide bond formation in secreted proteins. We thus tentatively propose a role for CutRS in sensing and responding to protein misfolding outside the cell. Since actinorhodin can oxidise cysteine residues and induce disulphide bond formation in proteins its over production in the ∆cutRS mutant may be a response to protein misfolding on the extracellular face of the membrane.

ORGANISM(S): Streptomyces coelicolor

PROVIDER: GSE225370 | GEO | 2023/06/12

REPOSITORIES: GEO

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Project description:Background The genomes of Streptomyces coelicolor and Streptomyces lividans bear a considerable degree of orthology. While S. coelicolor is the model streptomycete for studying antibiotic synthesis and differentiation, S. lividans is almost exclusively considered as the preferred host, among actinomycetes, for cloning and expression of exogenous DNA. We used whole genome microarrays as a comparative genomics tool for identifying the subtle yet crucial differences between these two chromosomes. Results We identified five large S. coelicolor genomic islands (≥25 kb) and 18 smaller islets absent in S. lividans chromosome. Many of these regions show anomalous GC bias and codon usage patterns. Six of them are in close vicinity of tRNA genes while nine are flanked with near perfect repeat sequences indicating that these are probable recent evolutionary acquisitions into S. coelicolor. Embedded within these segments are at least four DNA methylases and two probable methyl-sensing restriction endonucleases. Comparison with S. coelicolor transcriptome and proteome data revealed that some of the missing genes are active during the course of growth and differentiation in S. coelicolor. In particular, a pair of methylmalonyl CoA mutase (mcm) genes involved in polyketide precursor biosynthesis, an acyl-CoA dehydrogenase implicated in timing of actinorhodin synthesis and bldB, a developmentally significant regulator whose mutation causes complete abrogation of antibiotic synthesis belong to this category. Conclusion Our findings provide tangible hints for elucidating the genetic basis of important phenotypic differences between these two streptomycetes. Importantly, absence of certain genes in S. lividans identified here could potentially explain the relative ease of DNA transformations or the conditional lack of actinorhodin synthesis in S. lividans. Further genetic studies based on these results will enable one to target specific sequences in the genetically well-characterized S. coelicolor to adapt it for industrial processes. Keywords: Comparative Genomic Hybridization