Fungal iron homeostasis with a focus on Aspergillus fumigatus

Misslinger, Matthias; Hortschansky, Peter; Brakhage, Axel A.; Haas, Hubertus

doi:10.1016/j.bbamcr.2020.118885

Cited by 73 publications

(63 citation statements)

References 264 publications

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“…Here, we showed that CrzA binds to the promoter regions of most genes in siderophore BGC. As siderophores are involved in iron acquisition (Misslinger et al, 2020), and several SMs are responsive to changes in iron levels (Wiemann et al, 2014) we propose that CrzA (and calcium signaling) is involved in the iron homeostasis process, a role never reported before. Besides iron acquisition, the siderophores, along with gliotoxin, have an essential role in oxidative defense (Schrettl et al, 2007;Schrettl et al, 2010).…”

Section: Discussionmentioning

confidence: 61%

Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin

Colabardini

Wang

Dong

et al. 2021

Preprint

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Aspergillus fumigatus is the main causative agent of invasive pulmonary aspergillosis (IPA), a severe disease that affects immunosuppressed patients worldwide. The fungistatic drug caspofungin is the second line therapy against IPA but has increasingly been used against clinical strains that are resistant to azoles, the first line antifungal therapy. In high concentrations, caspofungin induces a tolerance phenotype with partial reestablishment of fungal growth called caspofungin paradoxical effect (CPE), resulting from a change in the composition of the cell wall. An increasing number of studies has shown that different isolates of A. fumigatus exhibit phenotypic heterogeneity, including heterogeneity in their CPE response. To gain insights into the underlying molecular mechanisms of CPE response heterogeneity, we analyzed the transcriptomes of two A. fumigatus reference strains, Af293 and CEA17, exposed to low and high caspofungin concentrations. We found that there is a core transcriptional response that involves genes related to cell wall remodeling processes, mitochondrial function, transmembrane transport, and amino acid and ergosterol metabolism, and a variable response related to secondary metabolite (SM) biosynthesis and iron homeostasis. Specifically, we show here that the overexpression of a SM pathway that works as an iron chelator extinguishes the CPE in both backgrounds, whereas iron depletion is detrimental for the CPE in Af293 but not in CEA17. We next investigated the function of the transcription factor CrzA, whose deletion was previously shown to result in heterogeneity in the CPE response of the Af293 and CEA17 strains. We found that CrzA constitutively binds to and modulates the expression of several genes related to processes involved in caspofungin tolerance, and that crzA deletion differentially impacts the SM production and growth of Af293 and CEA17. As opposed to the ? crzA CEA17 mutant, the ? crzA Af293 mutant fails to activate cell wall remodeling genes upon caspofungin exposure, which most likely severely affects its macrostructure and extinguishes its CPE. This work describes how heterogeneity in the response to an antifungal agent between A. fumigatus strains stems from heterogeneity in the function of a transcription factor and its downstream target genes.

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Section: Discussionmentioning

confidence: 61%

Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin

Colabardini

Wang

Dong

et al. 2021

Preprint

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“…The CBC:HapX complex, discovered in the early 2000s [ 38 ] and molecularly characterized a few years later [ 20 ], is essential for the adaptation to different iron availability in filamentous fungi and yeasts [ 21 , 22 , 39 , 40 , 41 , 42 ]. Because HapX-mediated adaptation to iron deficiency is essential for virulence both in animal and plant pathogens [ 11 , 12 , 13 , 14 , 15 ], the study of this bZIP transcription factor has aroused a lot of interest.…”

Section: Discussionmentioning

confidence: 99%

“…HapX CRR-A and CRR-B are crucial for this response while the C-terminal domain is responsible for the adaptation to iron starvation [ 17 ] ( Figure 1 ). Over the past two decades, a lot of effort has been put into the investigation of HapX mode of action, transcriptional regulation and iron-sensing mechanism [ 18 , 19 , 21 , 23 , 39 ]; however, little is known about its regulation at the protein level. Here, we found that there is considerable post-translational regulation of HapX.…”

Section: Discussionmentioning

confidence: 99%

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

López‐Berges

Scheven

Hortschansky

et al. 2021

IJMS

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The airborne fungus Aspergillus fumigatus causes opportunistic infections in humans with high mortality rates in immunocompromised patients. Previous work established that the bZIP transcription factor HapX is essential for virulence via adaptation to iron limitation by repressing iron-consuming pathways and activating iron acquisition mechanisms. Moreover, HapX was shown to be essential for transcriptional activation of vacuolar iron storage and iron-dependent pathways in response to iron availability. Here, we demonstrate that HapX has a very short half-life during iron starvation, which is further decreased in response to iron, while siderophore biosynthetic enzymes are very stable. We identified Fbx22 and SumO as HapX interactors and, in agreement, HapX post-translational modifications including ubiquitination of lysine161, sumoylation of lysine242 and phosphorylation of threonine319. All three modifications were enriched in the immediate adaptation from iron-limiting to iron-replete conditions. Interfering with these post-translational modifications, either by point mutations or by inactivation, of Fbx22 or SumO, altered HapX degradation, heme biosynthesis and iron resistance to different extents. Consistent with the need to precisely regulate HapX protein levels, overexpression of hapX caused significant growth defects under iron sufficiency. Taken together, our results indicate that post-translational regulation of HapX is important to control iron homeostasis in A. fumigatus.

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“…Some siderophores are endogenous in the pathogens, while others are secreted outside the pathogen. Aspergillus fumigatus secretes two siderophores—fusarinine C and triacetylfusarinine C—in addition to two endogenous siderophores it possesses [ 36 , 37 ]. In fungi, siderophore–iron transporters in the fungal membrane transport secreted siderophores which have chelated iron from the host into the fungal cell.…”

Section: Pet Imagingmentioning

confidence: 99%

Radionuclide Imaging of Fungal Infections and Correlation with the Host Defense Response

Ankrah

Sathekge

Dierckx

et al. 2021

JoF

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The human response to invading fungi includes a series of events that detect, kill, or clear the fungi. If the metabolic host response is unable to eliminate the fungi, an infection ensues. Some of the host response’s metabolic events to fungi can be imaged with molecules labelled with radionuclides. Several important clinical applications have been found with radiolabelled biomolecules of inflammation. 18F-fluorodeoxyglucose is the tracer that has been most widely investigated in the host defence of fungi. This tracer has added value in the early detection of infection, in staging and visualising dissemination of infection, and in monitoring antifungal treatment. Radiolabelled antimicrobial peptides showed promising results, but large prospective studies in fungal infection are lacking. Other tracers have also been used in imaging events of the host response, such as the migration of white blood cells at sites of infection, nutritional immunity in iron metabolism, and radiolabelled monoclonal antibodies. Many tracers are still at the preclinical stage. Some tracers require further studies before translation into clinical use. The application of therapeutic radionuclides offers a very promising clinical application of these tracers in managing drug-resistant fungi.

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Fungal iron homeostasis with a focus on Aspergillus fumigatus

Cited by 73 publications

References 264 publications

Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin

Heterogeneity in the transcriptional response of the human pathogen Aspergillus fumigatus to the antifungal agent caspofungin

The bZIP Transcription Factor HapX Is Post-Translationally Regulated to Control Iron Homeostasis in Aspergillus fumigatus

Radionuclide Imaging of Fungal Infections and Correlation with the Host Defense Response

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