The A-factor regulatory cascade and cAMP in the regulation of physiological and morphological development in...

In the A-factor regulatory cascade leading to the onset of streptomycin biosynthesis and aerial mycelium formation in Streptomyces griseus, the A-factor receptor protein (ArpA) serves as a DNA-binding repressor and A-factor releases the repression by binding to ArpA and dissociating it from the DNA. Mutants defective in arpA therefore produce streptomycin and aerial hyphae in the absence of A-factor. A gene that inhibits streptomycin production and aerial hyphae formation in an arpA mutant was cloned on a high-copy-number plasmid and found to encode a eukaryotic-type adenylate cyclase (CyaA). Consistent with this, an exogenous supply of cAMP at high concentration almost abolished streptomycin production and aerial hyphae formation. On the other hand, cAMP at lower concentrations stimulated or accelerated these developmental processes. The effects of cAMP were detectable only in arpA mutants, and not in the wild -type strain; an exogenous supply of cAMP or cyaA disruption in the wild-type strain caused almost no effect on these phenotypes. Thus the effects of cAMP became apparent only in the arpA-defective background. cAMP at high concentrations inhibited stringent response factor ppGpp production, which is important for the onset of antibiotic biosynthesis. cAMP also influenced the timing of tyrosine phosphorylation of more than nine proteins. These findings show that a cAMP regulatory relay for physiological and morphological development functions in a concerted and interdependent way with other signal transduction pathways.