Heat Shock Repressor HspR Directly Controls Avermectin Production, Morphological Development, and HO Stress Response in Streptomyces Avermitilis

The heat shock response (HSR) is a universal cellular response that promotes survival following temperature increase. In filamentous , which accounts for ∼70% of commercial antibiotic production, HSR is regulated by transcriptional repressors; in particular, the widespread MerR-family regulator HspR has been identified as a key repressor. However, functions of HspR in other biological processes are unknown. The present study demonstrates that HspR pleiotropically controls avermectin production, morphological development, and heat shock and HO stress responses in the industrially important species Streptomyces avermitilis. HspR directly activated structural genes ( and ) and HO stress-related genes (, , , , , and ), whereas it directly repressed heat shock genes (HSGs) (the operon, , , and ) and developmental genes (, , and ). HspR interacted with PhoP (response regulator of the widespread PhoPR two-component system) at to corepress the important operon. PhoP exclusively repressed target HSGs (, , and ) different from those of HspR (, , and ). A consensus HspR-binding site, 5'-TTGANBBNNHNNNDSTSHN-3', was identified within HspR target promoter regions, allowing prediction of the HspR regulon involved in broad cellular functions. Taken together, our findings demonstrate a key role of HspR in the coordination of a variety of important biological processes in species. Our findings are significant to clarify the molecular mechanisms underlying HspR function in antibiotic production, development, and HO stress responses through direct control of its target genes associated with these biological processes. HspR homologs described to date function as transcriptional repressors but not as activators. The results of the present study demonstrate that HspR acts as a dual repressor/activator. PhoP cross talks with HspR at to coregulate the heat shock response (HSR), but it also has its own specific target heat shock genes (HSGs). The novel role of PhoP in the HSR further demonstrates the importance of this regulator in . Overexpression of strongly enhanced avermectin production in Streptomyces avermitilis wild-type and industrial strains. These findings provide new insights into the regulatory roles and mechanisms of HspR and PhoP and facilitate methods for antibiotic overproduction in species.