Regulation of the AbrA1/A2 two-component system in Streptomyces coelicolor.: An heterologous host for antibiotic production

Abstract

Two-Component Systems (TCSs) are the most important transduction signal mechanism in bacteria, allowing the translation environmental or nutritional changes into a regulatory readout. Typically, TCSs comprise a membrane-bound histidine kinase (HK), which senses specific environmental stimuli, and a cognate regulator (RR), which mediates the cellular response, mainly through the transcriptional regulation of target genes. The TCS AbrA1/A2 from Streptomyces coelicolor M145 is a negative regulator of antibiotic production and morphological differentiation. In this work we show that it is able to auto-regulate its expression exerting a positive induction of its own operon promoter and that its activation is dependent on the presence of iron (Fe2+). The overexpression of the abrA2 response regulator (RR) gene in the mutant ∆abrA1/A2 results in a toxic phenotype. The reason is an excess of phosphorylated AbrA2, as shown by phosphoablative and hosphomimetic AbrA2 mutants. Therefore, non-cognate histidine kinases (HKs) may be responsible for AbrA2 phosphorylation in vivo. The results points out that, in the parent strain S. coelicolor M145, the correct amount of phosphorylated AbrA2 is adjusted through the phosphorylation-dephosphorylation activity rate of the HK AbrA1. Finally, in order to test biotechnological applications of the ∆abrA1/A2 strain, we demonstrate that the production of the anti-tumoral oviedomycin is duplicated in this strain when compared with the production obtained in the wild type, showing that this strain is a good host for heterologous antibiotic production. Therefore, this genetically modified strain could be interesting for biotechnology industries.