Regulation of iron-sulphur cluster homeostasis through transcriptional control of the Isc pathway by [2Fe-2S]-IscR in Escherichia coli

FeS clusters are essential across the biological world, yet how cells regulate expression of FeS cluster biogenesis pathways to cope with changes in FeS cluster demand is not well understood. Here, we describe the mechanism by which IscR, a [2Fe2S] cluster-containing regulator of Escherichia coli, adjusts the synthesis of the Isc FeS biogenesis pathway to maintain FeS homeostasis. Our data indicate that a negative feedback loop operates to repress transcription of the iscRSUAhscBAfdx operon, encoding IscR and the Isc machinery, through binding of [2Fe2S]IscR to two upstream binding sites. IscR was shown to require primarily the Isc pathway for synthesis of its FeS cluster, providing a link between IscR activity and demands for FeS clusters through the levels of the Isc system. Surprisingly, the isc operon was more repressed under anaerobic conditions, indicating increased FeS cluster occupancy of IscR and decreased FeS cluster biogenesis demand relative to aerobic conditions. Consistent with this notion, overexpression of a FeS protein under aerobic conditions, but not under anaerobic conditions, led to derepression of PiscR. Together, these data show how transcriptional control of iscRSUAhscBAfdx by [2Fe2S]IscR allows E.?coli to respond efficiently to varying FeS demands.