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The quorum-sensing system, consisting of an autoregulator synthase (AfsA or Aco homolog) and an autoregulator receptor (ArpA homolog), has been reported to be universally involved in regulating secondary metabolism in streptomycetes. Although the autoregulator synthase is thought to activate antibiotic production, the activation pathway remains poorly understood.  Streptomyces cyaneogriseus  ssp.  noncyanogenus  NMWT1 produces nemadectin, which is widely used as a biopesticide and veterinary drug due to its potent nematocidal activity. Here, we identified the Aco/ArpA-like system ScyA1/ScyR1, the ArpA homolog ScyR2 and the AfsA/ArpA-like system ScyA3/ScyR3 as important regulators of nemadectin production in NMWT1. Genetic experiments revealed that these five genes positively regulate nemadectin production, with  scyA1  and  scyR1  having the most potent effects. Importantly, ScyA1 is an upstream regulator of  scyR1  and promotes nemadectin production and sporulation by activating  scyR1  transcription. Intriguingly,  scyR1  silencing in NMWT1 up-regulated 12 of the 17 secondary metabolite biosynthetic core genes present in the NMWT1 genome, suggesting that ScyR1 mainly to be a repressor of secondary metabolism. In conclusion, our findings unveiled the regulatory pathways adopted by the quorum-sensing system, and provided the basis for a method to enhance antibiotic production and to activate the expression of cryptic biosynthetic gene clusters.

frontiers in bioengineering and biotechnology

Elucidation of the Activation Pathways of ScyA1/ScyR1, an Aco/ArpA-Like System That Regulates the Expression of Nemadectin and Other Secondary Metabolic Biosynthetic Genes