A coherent feed-forward loop fine-tunes KatG to maintain redox homeostasis in mycobacteria

Bacteria survive and reproduce in fluctuating environments by balancing their basic physiological needs, such as relying on iron-containing enzymes to detoxify reactive oxygen species (ROS) while conserving scarce iron. Understanding the regulatory networks that balance these conflicting needs is key to deciphering bacterial adaptability. Here, we identify a coherent feed-forward loop in mycobacteria that integrates the transcriptional regulator FurA3, the small RNA MrsI, RNA sponge FutR, and the catalase-peroxidase KatG. This circuit fine-tunes antioxidant responses according to iron availability. Under iron limitation, the iron-containing enzyme KatG is dually repressed by FurA3 transcriptionally and by MrsI post-transcriptionally, which conserves iron at the cost of antioxidant capacity. However, when iron deprivation coincides with oxidative stress, the circuit triggers an emergency response: H2O2 inactivates FurA3, relieving transcriptional repression of katG and futR, while induced FutR sequesters MrsI to post-transcriptionally derepress katG expression, enabling rapid KatG synthesis for effective peroxide detoxification. Our findings reveal a tightly regulated network that allows mycobacteria to balance iron homeostasis and oxidative stress defense, providing mechanistic insights into bacterial physiological trade-offs.