How Is Fe-S Cluster Formation Regulated?

Abstract

Iron-sulfur (Fe-S) clusters are fundamental to numerous biological processes in most organisms, but these protein cofactors can be prone to damage by various oxidants (e.g., O2, reactive oxygen species, and reactive nitrogen species) and toxic levels of certain metals (e.g., cobalt and copper). Furthermore, their synthesis can also be directly influenced by the level of available iron in the environment. Consequently, the cellular need for Fe-S cluster biogenesis varies with fluctuating growth conditions. To accommodate changes in Fe-S demand, microorganisms employ diverse regulatory strategies to tailor Fe-S cluster biogenesis according to their surroundings. Here, we review the mechanisms that regulate Fe-S cluster formation in bacteria, primarily focusing on control of the Isc and Suf Fe-S cluster biogenesis systems in the model bacterium Escherichia coli.

Keywords: Fe-S; Isc pathway; Suf pathway; homeostasis; iron-sulfur cluster; regulation.

Figure 1

In Escherichia coli, the cysteine desulfurase IscS plays a major role in providing sulfur for several pathways. In contrast, the cysteine desulfurase SufS appears to be specifically dedicated to Fe-S cluster biogenesis under conditions of stress. Indicated by arrows are known examples of proteins within sulfur-utilizing pathways that make direct protein-protein interactions with IscS or SufS.

Figure 2

Regulation of Isc-mediated Fe-S cluster biogenesis occurs at multiple levels.

Figure 3

Transcriptional regulation of the suf and isc operons under various growth conditions. Under nonstress conditions, transcriptional repression of the suf and isc operons is mediated by Fe²⁺-Fur and holo-IscR, respectively. In contrast, under conditions of iron limitation or oxidative stress, Fur and IscR are predicted to be primarily in their apo-protein forms. This results in derepression of the isc operon, which in turn results in elevated levels of apo-IscR. As apo-Fur is inactive for DNA binding, this allows apo-IscR to bind the suf promoter region to activate transcription. Additionally, oxidative stress leads to activation of OxyR, which in conjunction with the DNA-bending protein IHF promotes suf transcription. Although not depicted here, the Isc pathway is also subject to additional forms of regulation, such as differential degradation of the isc mRNA transcript by RyhB when iron is limiting and direct inactivation of the Isc machinery by various oxidants (Figure 2).