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σR (SigR) is an alternative sigma factor that enables gene expression in Streptomyces coelicolor to cope with thiol oxidation and antibiotic stresses. Its activity is repressed by a zinc‐containing anti‐sigma (ZAS) factor RsrA that senses thiol oxidants and electrophiles. Inactivation of RsrA by disulfide formation has been well studied. Here we investigated another pathway of RsrA inactivation by electrophiles. Mass spectrometry revealed alkylation of RsrA in vivo by N‐ethylmaleimide (NEM) at C61 and C62 located in the C‐terminal loop. Substitution mutation (C61S/C62S) in RsrA decreased the induction of σR target genes by electrophiles and made cells more sensitive to electrophiles. In contrast to stable protein of oxidized RsrA, alkylated RsrA is subjected to degradation partly mediated by ClpP proteases. RsrA2, a redox‐sensitive homolog of RsrA in S. coelicolor lacking cysteine in the terminal loop, did not respond to electrophiles. However, redox‐sensitive RsrA homologs in other Actinobacteria also harboring terminal loop cysteines all responded to electrophiles. These results indicate that the activity of RsrA can be modulated via cysteine alkylation, apart from disulfide formation of zinc‐coordinating cysteines. This pathway expands the spectrum of signals that the σR‐RsrA system can sense and reveals another intricate regulatory layer for optimal survival of Actinobacteria.
RsrA, a zinc‐containing anti‐sigma factor that responds to oxidative stress by forming disulfide bonds, can also responds to electrophiles by alkylating its C‐terminal loop cysteine(s) located distantly from the zinc coordination site. The alkylated anti‐sigma factor allows σR‐specific gene expression and is degraded by ClpP1/P2 protease system that is a member of the σR regulon. This phenomenon is conserved widely among actinomycetes.