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

<jats:title>Summary</jats:title><jats:p>Avermectins produced by <jats:italic>Streptomyces avermitilis</jats:italic> are effective anthelmintic agents. The autoregulatory signalling molecule that triggers avermectin biosynthesis is a novel butenolide‐type molecule, avenolide, rather than common γ‐butyrolactones (GBLs). We identified AvaR2, a pseudo GBL receptor homologue, as an important repressor of avermectin and avenolide biosynthesis and cell growth. AvaR2 directly repressed transcription of <jats:italic>aveR</jats:italic> (the <jats:italic>ave</jats:italic> cluster‐situated activator gene), <jats:italic>aco</jats:italic> (a key gene for avenolide biosynthesis), its own gene (<jats:italic>avaR2</jats:italic>) and two other GBL receptor homologous genes (<jats:italic>avaR1</jats:italic> and <jats:italic>avaR3</jats:italic>) by binding to their promoter regions. The <jats:italic>aveR</jats:italic> promoter had the highest affinity for AvaR2. A consensus 18 bp ARE (<jats:styled-content>a</jats:styled-content>uto<jats:styled-content>r</jats:styled-content>egulatory <jats:styled-content>e</jats:styled-content>lement)‐like sequence was found in the AvaR2‐binding regions of these five target genes. Eleven novel AvaR2 targets were identified, including genes involved in primary metabolism, ribosomal protein synthesis, and stress responses. AvaR2 bound and responded to endogenous avenolide and exogenous antibiotics jadomycin B (JadB) and aminoglycosides to modulate its DNA‐binding activity. Our findings help to clarify the roles of pseudo GBL receptors as pleiotropic regulators and as receptors for new type autoregulator and exogenous antibiotic signal. A pseudo GBL receptor‐mediated antibiotic signalling transduction system may be a common strategy that facilitates <jats:italic>Streptomyces</jats:italic> interspecies communication and survival in complex environments.</jats:p>