Functional transitions of the Aspergillus fumigatus iron regulator HapX are governed by conserved domains cooperatively binding [2Fe-2S] clusters
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PROVIDER: PRJNA1208963 | ENA |
REPOSITORIES: ENA
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Project description: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 different propensities of four phylogenetically conserved cysteine-rich regions (CRRs) to coordinate [2Fe-2S] clusters resulting in cumulative occupancies depending on iron availability. The iron starvation state features no [2Fe-2S] clusters in any of the CRRs, the iron sufficiency/”neutral” state features clusters in CRR-B and/or -C, and the iron excess state has clusters in CRR-A, -B, and -C, while CRR-D plays a minor role. Combinatorial mutation of CRR-B and -C inhibited growth by locking HapX in the iron starvation state, leading to uncontrolled iron uptake and repression of iron-consuming pathways and iron detoxification. This growth defect was partially rescued by removing the C-terminal 27 amino acids, which are crucial for the iron starvation state and contain a degron. Noteworthy, the HapX iron starvation state induced several gene clusters encoding secondary metabolites.
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Project description:The human mitochondrial ribosome contains three [2Fe-2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play structural roles during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the expression of Fe-S cluster biosynthetic and delivery factors on mitoribosome stability. We have found that the mitoribosome receives its [2Fe-2S] clusters from the GLRX5-BOLA3. Additionally, the assembly of the small subunit depends on METTL17, recently reported to contain a [4Fe-4S] cluster, which we found to be inserted via ISCA1-NFU1. Consistently, fibroblasts from patients suffering from “multiple mitochondrial dysfunction” syndrome due to mutations in BOLA3 or NFU1 display previously unrecognized attenuation of mitochondrial protein synthesis that contributes to their cellular and pathophysiological phenotypes. Finally, we report that, in addition to their structural role, the mitoribosomal [2Fe-2S] clusters sense changes in the redox environment. In this way, the mitoribosome checks the availability and stability of mitochondrial Fe-S clusters to regulate organellar protein synthesis accordingly.
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Project description:To sustain iron homeostasis, microorganisms have evolved fine-tuned mechanisms for uptake, storage and detoxification of the essential metal iron. In the human pathogen Aspergillus fumigatus, the fungal-specific bZIP-type transcription factor HapX coordinates adaption to both iron starvation and iron excess and is thereby crucial for virulence. Previous studies indicated that a HapX homodimer interacts with the CCAAT-binding complex (CBC) to cooperatively bind bipartite DNA motifs; however, the significance of the HapX and CBC interaction and the mode of HapX-DNA recognition had not been resolved. In this study, we characterized the genome-wide binding profiles of HapX using the chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq). Our ChIP-seq results, in combination with in vitro surface plasmon resonance analysis, phylogenetic comparison, and genetic analysis, revealed an astonishing plasticity of the CBC:HapX DNA-recognition mode.
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