O₂ availability impacts iron homeostasis in Escherichia coli.

The ferric-uptake regulator (Fur) is an Fe²⁺-responsive transcription factor that coordinates iron homeostasis in many bacteria. Recently, we reported that expression of the Escherichia coli Fur regulon is also impacted by O₂ tension. Here, we show that for most of the Fur regulon, Fur binding and transcriptional repression increase under anaerobic conditions, suggesting that Fur is controlled by O₂ availability. We found that the intracellular, labile Fe²⁺ pool was higher under anaerobic conditions compared with aerobic conditions, suggesting that higher Fe²⁺ availability drove the formation of more Fe²⁺-Fur and, accordingly, more DNA binding. O₂ regulation of Fur activity required the anaerobically induced FeoABC Fe²⁺ uptake system, linking increased Fur activity to ferrous import under iron-sufficient conditions. The increased activity of Fur under anaerobic conditions led to a decrease in expression of ferric import systems. However, the combined positive regulation of the feoABC operon by ArcA and FNR partially antagonized Fur-mediated repression of feoABC under anaerobic conditions, allowing ferrous transport to increase even though Fur is more active. This design feature promotes a switch from ferric import to the more physiological relevant ferrous iron under anaerobic conditions. Taken together, we propose that the influence of O₂ availability on the levels of active Fur adds a previously undescribed layer of regulation in maintaining cellular iron homeostasis.

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