Heat shock response (HSR) is a universal cellular response that promotes survival following temperature increase. In filamentous
Streptomyces
, which account for ∼70% 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 H
2
O
2
stress responses in industrially important species
S. avermitilis
. HspR directly activated
ave
structural genes (
aveA1
,
aveA2
) and H
2
O
2
stress-related genes (
katA1
,
catR
,
katA3
,
oxyR
,
ahpC
,
ahpD
), whereas it directly repressed heat shock genes (HSGs) (
dnaK1-grpE1-dnaJ1-hspR
operon,
clpB1p
,
clpB2p
,
lonAp
) and developmental genes (
wblB
,
ssgY
,
ftsH
). HspR interacted with PhoP (response regulator of the widespread PhoPR two-component system) at
dnaK1p
to co-repress the important
dnaK1-grpE1-dnaJ1-hspR
operon. PhoP exclusively repressed target HSGs (
htpG
,
hsp18_1
,
hsp18_2
) different from those of HspR (
clpB1p
,
clpB2p
,
lonAp
). 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 coordination of a variety of important biological processes in
Streptomyces
species.
IMPORTANCE
Our findings are significant to clarify the molecular mechanisms underlying HspR function in
Streptomyces
antibiotic production, development, and H
2
O
2
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. Results of the present study demonstrate that HspR acts as a dual repressor/activator. PhoP was shown to crosstalk with HspR at
dnaK1p
to co-regulate HSR and have its exclusive target HSGs. The novel role of PhoP in HSR further demonstrates the importance of this regulator in
Streptomyces
. Overexpression of
hspR
strongly enhanced avermectin production in
S. 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
Streptomyces
species.
Role of Phosphopantetheinyl Transferase Genes in Antibiotic Production by Streptomyces coelicolor
