Iron Homeostasis Mechanisms in Fungal Pathogens

Iron is indispensable for fundamental cellular processes in fungi, yet its redox activity renders excess amounts toxic. Pathogenic fungi encounter iron scarcity within host tissues, as vertebrate hosts tightly sequester iron to restrain microbial growth. To overcome this challenge, fungal pathogens deploy two principal acquisition systems: high‐affinity siderophore production and reductive iron assimilation. Siderophores are low‐molecular‐mass chelators secreted to scavenge ferric iron, which is then imported via specific transporters. Reductive iron assimilation involves extracellular reduction of ferric to ferrous iron, followed by uptake through membrane permeases. Intracellularly, fungi store excess iron in vacuoles or bound to proteins to buffer fluctuations. Sophisticated transcriptional circuits, centred on the GATA‐type regulator SreA and the bZIP factor HapX, reciprocally control uptake and consumption pathways: SreA represses siderophore biosynthesis and reductive uptake under iron‐replete conditions, whereas HapX suppresses iron‐dependent metabolic routes during starvation while activating siderophore genes. Recent work has uncovered layers of epigenetic control and cross‐talk with stress responses, further refining iron adaptation. These homeostatic mechanisms are intimately linked to fungal virulence, since disruption of siderophore pathways or regulatory nodes attenuates pathogenicity across diverse hosts. Translational applications exploit the fungal specificity of siderophore machinery for diagnostic imaging and novel antifungal strategies, underscoring the global significance of understanding iron homeostasis in fungal pathogens.

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Iron Homeostasis Mechanisms in Fungal Pathogens publication trend

The graph below shows the total number of articles in iron homeostasis mechanisms in fungal pathogens across all publications each year (not limited to Nature Index journals).

Technical terms

Siderophore: Low‐molecular‐mass iron‐chelating compound secreted by fungi to scavenge ferric iron under limiting conditions.

Reductive iron assimilation: Mechanism whereby extracellular ferric iron is enzymatically reduced to ferrous iron for uptake through specific permeases.

SreA: GATA‐type transcription factor that represses iron‐uptake genes during iron sufficiency to prevent toxicity.

HapX: bZIP‐type transcription factor that represses iron‐consuming pathways and activates siderophore biosynthesis under starvation.

H2A.Z deposition: Incorporation of the histone variant H2A.Z into nucleosomes, a process that can modulate gene expression in response to iron levels.

References

1. HapX-mediated H2B deub1 and SreA-mediated H2A.Z deposition coordinate in fungal iron resistance. Nucleic Acids Research (2023).
2. Biomimetic Analogues of the Desferrioxamine E Siderophore for PET Imaging of Invasive Aspergillosis: Targeting Properties and Species Specificity. Journal of Medicinal Chemistry (2024).
3. Fungal siderophore metabolism with a focus on Aspergillus fumigatus: impact on biotic interactions and potential translational applications. Essays in Biochemistry (2023).