A widespread actinobacterial G protein system regulates production of specialized metabolites in Streptomyces coelicolor

Actinobacterial G protein systems (AGPSs), encoded by operons called conservons, are regulatory systems that are broadly distributed within Actinomycetota. AGPSs contain a minimum of four proteins, namely, a sensor histidine kinase, a small Ras-like GTPase, a roadblock/MglB protein (likely a GTPase activating protein), and a protein that likely functions as a guanine-nucleotide exchange factor (GEF). While progress has been made in understanding AGPS function at the mechanistic level, the phylogenetic distribution of individual AGPSs and the genes and processes they regulate remain largely unmapped. Previously, the Cvn8 AGPS of Streptomyces coelicolor was found to influence expression of genes in multiple specialized metabolic pathways during interspecies interactions with other actinomycetes. However, the impact of the Cvn8 AGPS on specialized metabolism has not been assessed at the chemical level. Here, we investigated the phylogenetic distribution of the Cvn8 AGPS clade and assessed the impact of the Cvn8 AGPS on natural product biosynthesis using untargeted metabolomics. In a set of 485 actinobacterial genomes, we found that members of the clade that includes the Cvn8 AGPS from S. coelicolor are widely distributed in Actinomycetota known to produce specialized metabolites. We also found that in S. coelicolor , the pattern of specialized metabolite production varied in mutants lacking individual components of the Cvn8 AGPS. Specifically, normal production of the pigmented antibiotics actinorhodin and undecylprodiginine during interspecies interactions required cvnA8 and cvnF8 , while a Δ cvnD8 strain overproduced undecylprodiginine. Together, these results connect a widespread AGPS to control of specialized metabolism in a model actinomycete.