Sulfane Sulfur Posttranslationally Modifies the Global Regulator AdpA to Influence Actinorhodin Production and Morphological Differentiation of Streptomyces coelicolor

The transcription factor AdpA is a key regulator controlling both secondary metabolism and morphological differentiation in Streptomyces. Due to its critical functions, its expression undergoes multilevel regulations at transcriptional, posttranscriptional, and translational levels, yet no posttranslational regulation has been reported. Sulfane sulfur, such as hydro polysulfide (HS(n)H, n ≥ 2) and organic polysulfide (RS(n)H, n ≥ 2), is common inside microorganisms, but its physiological functions are largely unclear. Here, we discovered that sulfane sulfur posttranslationally modifies AdpA in Streptomyces coelicolor via specifically reacting with Cys(62) of AdpA to form a persulfide (Cys(62)-SSH). This modification decreases the affinity of AdpA to its self-promoter P(adpA), allowing increased expression of adpA, further promoting the expression of its target genes actII-4 and wblA. ActII-4 activates actinorhodin biosynthesis, and WblA regulates morphological development. Bioinformatics analyses indicated that AdpA-Cys(62) is highly conserved in Streptomyces, suggesting the prevalence of such modification in this genus. Thus, our study unveils a new type of regulation on the AdpA activity and sheds a light on how sulfane sulfur stimulates the production of antibiotics in Streptomyces.