ScbR- and ScbR2-mediated signal transduction networks coordinate complex physiological responses in Streptomyces coelicolor

Abstract

In model organism Streptomyces coelicolor, γ-butyrolactones (GBLs) and antibiotics were recognized as signalling molecules playing fundamental roles in intra- and interspecies communications. To dissect the GBL and antibiotic signalling networks systematically, the in vivo targets of their respective receptors ScbR and ScbR2 were identified on a genome scale by ChIP-seq. These identified targets encompass many that are known to play important roles in diverse cellular processes (e.g. gap1, pyk2, afsK, nagE2, cdaR, cprA, cprB, absA1, actII-orf4, redZ, atrA, rpsL and sigR), and they formed regulatory cascades, sub-networks and feedforward loops to elaborately control key metabolite processes, including primary and secondary metabolism, morphological differentiation and stress response. Moreover, interplay among ScbR, ScbR2 and other regulators revealed intricate cross talks between signalling pathways triggered by GBLs, antibiotics, nutrient availability and stress. Our work provides a global view on the specific responses that could be triggered by GBL and antibiotic signals in S. coelicolor, among which the main echo was the change of production profile of endogenous antibiotics and antibiotic signals manifested a role to enhance bacterial stress tolerance as well, shedding new light on GBL and antibiotic signalling networks widespread among streptomycetes.

AvaR2, a pseudo γ‐butyrolactone receptor homologue from Streptomyces avermitilis, is a pleiotropic repressor of avermectin and avenolide biosynthesis and cell growth

“…To decipher the AvaR2 regulon in S. avermitilis , we used the 18 bp AvaR2 consensus binding motif to scan the genome with the MAST/MEME web‐based application (http://meme-suite.org). The regulation region of genes was set as −600 to +100 bp relative to the translational start codon (Li et al ., ). One hundred putative AvaR2 target genes were identified having E ‐value ≤ 100 (the smaller the E ‐value, the greater the possibility) (Supporting Information Table S1).…”

Recent advances in understanding Streptomyces

“…This results in an integrated feedback and feedforward regulatory scheme that accounts for both the onset of the major period of jadomycin production and its subsequent down-regulation 66 . In S. coelicolor , genome-wide ChIP-seq analysis has revealed an extensive network of regulatory interactions centred on ScbR (GBL receptor) and ScbR2 (pseudo-GBL receptor that binds antibiotics) 107, 108 .…”

“…Thus, S. coelicolor can respond to the presence of another species by undergoing developmental changes and switching on antibiotic production. Another example of such a response has been documented for lidamycin biosynthesis in Streptomyces globisporus, involving a widely conserved TetR-like global activator of antibiotic production, AtrA 107 . AtrA directly activates lidamycin biosynthetic genes, but its activity is prevented by binding either a lidamycin biosynthetic intermediate, heptaene, or heterologously produced ACT 107 .…”

“…Another example of such a response has been documented for lidamycin biosynthesis in Streptomyces globisporus, involving a widely conserved TetR-like global activator of antibiotic production, AtrA 107 . AtrA directly activates lidamycin biosynthetic genes, but its activity is prevented by binding either a lidamycin biosynthetic intermediate, heptaene, or heterologously produced ACT 107 . Inter-species interactions affecting antibiotic production are proving to be widespread among streptomycetes: a large-scale study of inter-organism interactions revealed many cases of production of secondary metabolites induced by growth close to another species 115, 116 , and another study found that low levels of lincomycin induced ACT production by S. coelicolor 117 .…”

Enzyme-constrained models and omics analysis of Streptomyces coelicolor reveal metabolic changes that enhance heterologous production

“…This high expression level is likely due to the deletion of scbR2 (SCO6286), the last gene selected to be part of the cpk gene cluster (Bednarz et al, 2019). Besides regulation of the cpk cluster, ScbR2 binds upstream of several global regulators of development and secondary metabolism, including AfsK, SigR, NagE2, AtrA, and ArgR (Li et al, 2015). It also acts together with ScbR to regulate ScbA, which produces the y-butyrolactone SCB1.…”