The dual toxicity/essentiality of copper forces cells to maintain a tightly regulated homeostasis for this metal in all living organisms, from bacteria to humans. Consequently, many genes have previously been reported to participate in copper detoxification in bacteria. Myxococcus xanthus, a prokaryote, encodes many proteins involved in copper homeostasis that are differentially regulated by this metal. A σ factor of the ECF (extracytoplasmic function) family, CorE, has been found to regulate the expression of the multicopper oxidase cuoB, the P1B-type ATPases copA and copB, and a gene encoding a protein with a heavy-metal-associated domain. Characterization of CorE has revealed that it requires copper to bind DNA in vitro. Genes regulated by CorE exhibit a characteristic expression profile, with a peak at 2 h after copper addition. Expression rapidly decreases thereafter to basal levels, although the metal is still present in the medium, indicating that the activity of CorE is modulated by a process of activation and inactivation. The use of monovalent and divalent metals to mimic Cu(I) and Cu(II), respectively, and of additives that favor the formation of the two redox states of this metal, has revealed that CorE is activated by Cu(II) and inactivated by Cu(I). The activation/inactivation properties of CorE reside in a Cys-rich domain located at the C terminus of the protein. Point mutations at these residues have allowed the identification of several Cys involved in the activation and inactivation of CorE. Based on these data, along with comparative genomic studies, a new group of ECF σ factors is proposed, which not only clearly differs mechanistically from the other σ factors so far characterized, but also from other metal regulators.
Copper exerts a dual effect on living organisms. It is essential for life, but an excess provokes cell damage, forcing cells to maintain a regulated homeostasis for this metal. These two antagonistic biological effects of copper are clearly illustrated by two human genetic disorders, Menkes syndrome and Wilson disease, caused by deficiency or accumulation of this metal, respectively. Myxococcus xanthus, a soil-dwelling bacterium, also has to cope with changes in copper concentration in its environment. The large genome of this myxobacterium encodes many genes involved in copper homeostasis, all of which are differentially regulated, indicating that many regulators participate in copper homeostasis in this prokaryote. Here, we identify one of these regulators (CorE), which belongs to the family of the extracytoplasmic function (ECF) σ factors. We demonstrate that CorE represents a novel group of ECF σ factors and of metal regulators, because its activity is modulated by the redox state of copper. This ability resides in a Cys-rich domain, which has also been found in other σ factors of different bacterial phyla. Therefore, we propose that CorE is the first member of a mechanistically new group of ECF σ factors.