Positive and negative feedback regulatory loops of thiol-oxidative stress response mediated by an unstable isoform of &sgr;^R in actinomycetes

다국어 초록 (Multilingual Abstract)

<P>Summary</P><P>Alternate sigma factors provide an effective way of diversifying bacterial gene expression in response to environmental changes. In <I>Streptomyces coelicolor</I> where more than 65 sigma factors are predicted, &sgr;<SUP>R</SUP> is the major regulator for response to thiol-oxidative stresses. &sgr;<SUP>R</SUP> becomes available when its bound anti-sigma factor RsrA is oxidized at sensitive cysteine thiols to form disulphide bonds. &sgr;<SUP>R</SUP> regulon includes genes for itself and multiple thiol-reducing systems, which constitute positive and negative feedback loops respectively. We found that the positive amplification loop involves an isoform of &sgr;<SUP>R</SUP> (&sgr;<SUP>R′</SUP>) with an N-terminal extension of 55 amino acids, produced from an upstream start codon. A major difference between constitutive &sgr;<SUP>R</SUP> and inducible &sgr;<SUP>R′</SUP> is that the latter is markedly unstable (<I>t</I><SUB>1/2</SUB> ∼ 10 min) compared with the former (> 70 min). The rapid turnover of &sgr;<SUP>R′</SUP> is partly due to induced ClpP1/P2 proteases from the &sgr;<SUP>R</SUP> regulon. This represents a novel way of elaborating positive and negative feedback loops in a control circuit. Similar phenomenon may occur in other actinomycetes that harbour multiple start codons in the <I>sigR</I> homologous gene. We observed that <I>sigH</I> gene, the <I>sigR</I> orthologue in <I>Mycobacterium smegmatis</I>, produces an unstable larger isoform of &sgr;<SUP>H</SUP> upon induction by thiol-oxidative stress.</P>