SigR, a hub of multilayered regulation of redox and antibiotic stress responses

Abstract

Signal-specific activation of alternative sigma factors redirects RNA polymerase to induce transcription of distinct sets of genes conferring protection against the damage the signal and the related stresses incur. In Streptomyces coelicolor, σ^R (SigR), a member of ECF12 subfamily of Group IV sigma factors, responds to thiol-perturbing signals such as oxidants and electrophiles, as well as to translation-blocking antibiotics. Oxidants and electrophiles interact with and inactivate the zinc-containing anti-sigma factor, RsrA, via disulfide bond formation or alkylation of reactive cysteines, subsequently releasing σ^R for target gene induction. Translation-blocking antibiotics induce the synthesis of σ^R , via the WhiB-like transcription factor, WblC/WhiB7. Signal transduction via RsrA produces a dramatic transient response that involves positive feedback to produce more SigR as an unstable isoform ${\sigma }^{{\text{R}}^{\text{'}}}$ and negative feedbacks to degrade ${\sigma }^{{\text{R}}^{\text{'}}}$ , and reduce oxidized RsrA that subsequently sequester σ^R and ${\sigma }^{{\text{R}}^{\text{'}}}$ . Antibiotic stress brings about a prolonged response by increasing stable σ^R levels. The third negative feedback, which occurs via IF3, lowers the translation efficiency of the sigRp1 transcript that utilizes a non-canonical start codon. σ^R is a global regulator that directly activates > 100 transcription units in S. coelicolor, including genes for thiol homeostasis, protein quality control, sulfur metabolism, ribosome modulation and DNA repair. Close homologues in Actinobacteria, such as σ^H in Mycobacteria and Corynebacteria, show high conservation of the signal transduction pathways and target genes, thus reflecting the robustness of this type of regulation in response to redox and antibiotic stresses.