The σ R regulon of Streptomyces coelicolor A3(2) reveals a key role in protein quality control during disulphide stress

Abstract

Diamide is an artificial disulphide-generating electrophile that mimics an oxidative shift in the cellular thiol–disulphide redox state (disulphide stress). The Gram-positive bacteriumStreptomyces coelicolorsenses and responds to disulphide stress through theσR–RsrA system, which comprises an extracytoplasmic function (ECF) sigma factor and a redox-active anti-sigma factor. Known targets that aid in the protection and recovery from disulphide stress include the thioredoxin system and genes involved in producing the major thiol buffer mycothiol. Here we determine the global response to diamide in wild-type andsigRmutant backgrounds to understand the role ofσRin this response and to reveal additional regulatory pathways that allow cells to cope with disulphide stress. In addition to thiol oxidation, diamide was found to cause protein misfolding and aggregation, which elicited the induction of the HspR heat-shock regulon. Although this response isσR-independent,σRdoes directly control Clp and Lon ATP-dependent AAA(+) proteases, which may partly explain the reduced ability of asigRmutant to resolubilize protein aggregates.σRalso controlsmsrAandmsrBmethionine sulphoxide reductase genes, implying thatσR–RsrA is responsible for the maintenance of both cysteine and methionine residues during oxidative stress. This work shows that theσR–RsrA system plays a more significant role in protein quality control than previously realized, and emphasizes the importance of controlling the cellular thiol–disulphide redox balance.