RT Journal Article
SR Electronic
T1 Cooperative [2Fe-2S] cluster-binding regulates the functional transitions of the <em>Aspergillus fumigatus</em> iron regulator HapX for adaptation to iron starvation, sufficiency and excess
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2024.11.27.625597
DO 10.1101/2024.11.27.625597
A1 Oberegger, Simon
A1 Misslinger, Matthias
A1 Haas, Hubertus
YR 2024
UL http://biorxiv.org/content/early/2024/11/28/2024.11.27.625597.abstract
AB Accurate sensing of cellular iron levels is vital, as this metal is essential but toxic in excess. The iron-sensing transcription factor HapX is crucial for virulence of Aspergillus fumigatus, the predominant human mold pathogen. Its absence impairs growth under iron limitation and excess, but not under moderate iron availability, suggesting that HapX switches between three states to adapt to varying iron availability.This study suggests that the HapX state transitions are regulated by the different propensities of four phylogenetically conserved cysteine-rich regions (CRRs) to coordinate [2Fe-2S] clusters resulting in cumulative occupancies that depend on iron availability. In the iron starvation state, CRR-B and -C lack [2Fe-2S] clusters, the iron sufficiency/”neutral” state features clusters in CRR-B and/or -C and the iron excess state has clusters in all CRR-A, B, and -C, while CRR-D plays a minor role. Combinatorial mutation of CRR-B and -C blocked growth by locking HapX in the iron starvation state, leading to uncontrolled iron uptake, iron accumulation, repression of iron-consuming pathways and impaired iron detoxification. Loss of the C-terminal 27 amino acid region of HapX, which is crucial for the iron starvation state and was found to contain a degron, rescued the severe growth defect. Noteworthy, the - Fe state of HapX induced several gene clusters encoding secondary metabolites.Competing Interest StatementThe authors have declared no competing interest.BPSbathophenanthroline disulfonic acidCRRcysteine-rich region-Feiron-limiting condition+Feiron sufficient conditionhFeiron excess conditionPxylPxylose-inducible xylP promoterwtwild type;