Heme-iron acquisition in fungi

Roy, Udita; Kornitzer, Daniel

doi:10.1016/j.mib.2019.05.006

Cited by 33 publications

(27 citation statements)

References 57 publications

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“…In C. albicans, the heme uptake pathway is strongly induced under iron starvation conditions (Weissman and Kornitzer, 2004;Chen et al, 2011;Kuznets et al, 2014;Nasser et al, 2016;Roy and Kornitzer, 2019). While heme can in fact be used as an alternative iron source by C. albicans, the ability shown here to use external heme as a heme source would save the cells the need for the elemental iron required in heme synthesis, while in addition also saving the metabolic cost of protoporphyrin synthesis.…”

Section: Discussionmentioning

confidence: 88%

“…This raises the question whether, even in the presence of iron, C. albicans cells could utilize external heme. One striking observation is that, in addition to iron starvation conditions, the CFEM hemophores involved in heme uptake are also among the most strongly induced genes under hyphal induction conditions (Azadmanesh et al, 2017;Roy and Kornitzer, 2019). C. albicans is a dimorphic pathogen, capable of switching from a yeast to a hyphal (mold) morphology under a variety of conditions such as elevated temperature, the presence of serum, the bacterial and fungal cell wall precursor N-acetyl glucosamine, among others (Sudbery et al, 2004;Basso et al, 2019;Kornitzer, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…We wondered whether the lack of growth on hemoglobin could be due to a lack of induction of the heme-uptake pathway. Indeed, the known genes specifically required for extraction of heme from hemoglobin and heme uptake, the CFEM hemophore genes RBT5, PGA7 and CSA2, are among the highest-induced genes under iron starvation conditions (Lan et al, 2004;Weissman and Kornitzer, 2004;Chen et al, 2011;Roy and Kornitzer, 2019). We thus also tested growth on hemin and hemoglobin in medium supplemented with 1 mM ferrozine, an iron chelator that imposes partial iron starvation on the cells and causes induction of the heme uptake genes (Weissman and Kornitzer, 2004).…”

Section: Hemin and Hemoglobin Can Serve As Heme Sources For C Albicansmentioning

confidence: 99%

“…and Pga7 capture the heme and transfer it across the cell envelope to the endocytic pathway (Weissman and Kornitzer, 2004;Kuznets et al, 2014;Pinsky et al, 2020) (reviewed in (Roy and Kornitzer, 2019)). This pathway also requires parts of the ESCRT (Endosomal Sorting Complexes Required for Transport) system, an endocytosis-specific myosin, and the vacuolar ATPase (Weissman et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Using genetically encoded heme sensors to probe the mechanisms of heme uptake and homeostasis inCandida albicans

Weissman

Pinsky

Donegan

et al. 2020

Preprint

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Candida albicans is a major fungal pathogen that can utilize hemin and hemoglobin as iron sources in the iron-scarce host environment. While C. albicans is a heme prototroph, we show here that it can also efficiently utilize external heme as a cellular heme source. Using genetically encoded ratiometric fluorescent heme sensors, we show that heme extracted from hemoglobin and free hemin enter the cells with different kinetics. Heme supplied as hemoglobin is taken up via the CFEM (Common in Fungal Extracellular Membrane) hemophore cascade, and reaches the cytoplasm over several hours, whereas entry of free hemin via CFEM-dependent and independent pathways is much faster, less than an hour. To prevent an influx of extracellular heme from reaching toxic levels in the cytoplasm, the cells deploy Hmx1, a heme oxygenase. Hmx1 was previously suggested to be involved in utilization of hemoglobin and hemin as iron sources, but we find that it is primarily required to prevent heme toxicity. Taken together, the combination of novel heme sensors with genetic analysis revealed new details of the fungal mechanisms of heme import and homeostasis, necessary to balance the uses of heme as essential cofactor and potential iron source against its toxicity.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Hemin and Hemoglobin Can Serve As Heme Sources For C Albicansmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Using genetically encoded heme sensors to probe the mechanisms of heme uptake and homeostasis inCandida albicans

Weissman

Pinsky

Donegan

et al. 2020

Preprint

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“…Most iron in vertebrate hosts is present in heme, and heme-containing proteins such as hemoglobin and the haptoglobin-hemoglobin complex are potentially abundant sources of iron for fungal pathogens during disease (18). The mechanisms for acquisition and use of heme-iron sources are starting to be discovered in some fungi, including Aspergillus fumigatus, Candida albicans, Candida glabrata, C. neoformans, Schizosaccharomyces pombe, and Paracoccidioides brasiliensis (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). For example, studies in C. neoformans revealed important roles in heme use for endocytosis and endomembrane trafficking machinery, including the ESCRT proteins Vps22, Vps23, and Snf7, and proteins for clathrin-mediated endocytosis such as Chc1 (clathrin heavy chain 1), Las17 (a nucleation᎑promoting factor for actin assembly), and Rvs161/Rvs167 (vesicle scission proteins; amphiphysins) (25,26,28).…”

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confidence: 99%

A Cytoplasmic Heme Sensor Illuminates the Impacts of Mitochondrial and Vacuolar Functions and Oxidative Stress on Heme-Iron Homeostasis in Cryptococcus neoformans

Bairwa

Sánchez‐León

et al. 2020

mBio

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Pathogens must compete with hosts to acquire sufficient iron for proliferation during pathogenesis. The pathogenic fungus Cryptococcus neoformans is capable of acquiring iron from heme, the most abundant source in vertebrate hosts, although the mechanisms of heme sensing and acquisition are not entirely understood. In this study, we adopted a chromosomally encoded heme sensor developed for Saccharomyces cerevisiae to examine cytosolic heme levels in C. neoformans using fluorescence microscopy, fluorimetry, and flow cytometry. We validated the responsiveness of the sensor upon treatment with exogenous hemin, during proliferation in macrophages, and in strains defective for endocytosis. We then used the sensor to show that vacuolar and mitochondrial dysregulation and oxidative stress reduced the labile heme pool in the cytosol. Importantly, the sensor provided a tool to further demonstrate that the drugs artemisinin and metformin have heme-related activities and the potential to be repurposed for antifungal therapy. Overall, this study provides insights into heme sensing by C. neoformans and establishes a powerful tool to further investigate mechanisms of heme-iron acquisition in the context of fungal pathogenesis. IMPORTANCE Invasive fungal diseases are increasing in frequency, and new drug targets and antifungal drugs are needed to bolster therapy. The mechanisms by which pathogens obtain critical nutrients such as iron from heme during host colonization represent a promising target for therapy. In this study, we employed a fluorescent heme sensor to investigate heme homeostasis in Cryptococcus neoformans. We demonstrated that endocytosis is a key aspect of heme acquisition and that vacuolar and mitochondrial functions are important in regulating the pool of available heme in cells. Stress generated by oxidative conditions impacts the heme pool, as do the drugs artemisinin and metformin; these drugs have heme-related activities and are in clinical use for malaria and diabetes, respectively. Overall, our study provides insights into mechanisms of fungal heme acquisition and demonstrates the utility of the heme sensor for drug characterization in support of new therapies for fungal diseases.

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