Sphingolipids from the human fungal pathogen Aspergillus fumigatus

Fontaine, Thierry

doi:10.1016/j.biochi.2017.06.012

Cited by 19 publications

(14 citation statements)

References 84 publications

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“…The gene gsl-4 is a lac-1 paralog and ortholog of the gene LAG1 from Saccharomyces cerevisiae (Schorling et al, 2001) and lagA from Aspergillus sp. (Cheng et al, 2001; Fontaine, 2017), and is implicated in the inositol phosphorylceramide (IPC) synthesis pathway. But since this mutant showed no difference in its phenotype compared to the wt in respect to vegetative growth, conidiation and susceptibility to AMPs (data not shown), we decided to focus in this study on the characterization of the mutants of the GlcCer biosynthesis pathway rather than the IPC pathway.…”

Section: Resultsmentioning

confidence: 99%

“…The barrier function of the plasma membrane is crucial for cellular homeostasis and cell environment interactions. The activity of enzymes, transporters and receptors embedded in and along this lipid bilayer ensures important vital functions, such as cell wall synthesis, growth, cell polarity establishment, reproduction and optimal adaptation to environmental changes (Los and Murata, 2004; Fontaine, 2017). As such, any alteration of the lipid composition of the plasma membrane might impact the distribution, regulation, activity and signaling function of membrane proteins, with adverse effects on the fungal cell fitness.…”

Section: Introductionmentioning

confidence: 99%

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Membrane Sphingolipids Regulate the Fitness and Antifungal Protein Susceptibility of Neurospora crassa

et al. 2019

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The membrane sphingolipid glucosylceramide (GlcCer) plays an important role in fungal fitness and adaptation to most diverse environments. Moreover, reported differences in the structure of GlcCer between fungi, plants and animals render this pathway a promising target for new generation therapeutics. Our knowledge about the GlcCer biosynthesis in fungi is mainly based on investigations of yeasts, whereas this pathway is less well characterized in molds. We therefore performed a detailed lipidomic profiling of GlcCer species present in Neurospora crassa and comprehensively show that the deletion of genes encoding enzymes involved in GlcCer biosynthesis affects growth, conidiation and stress response in this model fungus. Importantly, our study evidences that differences in the pathway intermediates and their functional role exist between N. crassa and other fungal species. We further investigated the role of GlcCer in the susceptibility of N. crassa toward two small cysteine-rich and cationic antimicrobial proteins (AMPs), PAF and PAFB, which originate from the filamentous ascomycete Penicillium chrysogenum . The interaction of these AMPs with the fungal plasma membrane is crucial for their antifungal toxicity. We found that GlcCer determines the susceptibility of N. crassa toward PAF, but not PAFB. A higher electrostatic affinity of PAFB than PAF to anionic membrane surfaces might explain the difference in their antifungal mode of action.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Membrane Sphingolipids Regulate the Fitness and Antifungal Protein Susceptibility of Neurospora crassa

et al. 2019

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“…During the last two decades, GlcCer has been extensively described in a variety of fungi, such as Collectotrichum gloeosporioides , Fonsecaea pedrosoi , Cryptococcus neoformans , Candida albicans, and different species from the Scedosporium/Lomentospora complex [8,9,10,11,12,13,14]. These molecules have also been described in different Aspergillus species, such as Aspergillus fumigatus , Aspergillus oryzae , Aspergillus sojae , Aspergillus luchuensis, and Aspergillus awamori , presenting not only glucosylceramide but also galactosylceramides, showing that chemical composition may vary among fungi [15,16,17]. GlcCer has been shown to be a highly conserved structure among these fungi and to exert crucial roles in fungal morphological transitions, growth, and pathogenesis [8,9,10,11,12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Structural Differences Influence Biological Properties of Glucosylceramides from Clinical and Environmental Isolates of Scedosporium aurantiacum and Pseudallescheria minutispora

Caneppa

Meirelles

Rollin-Pinheiro

et al. 2019

JoF

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Scedosporium/Lomentospora complex is composed of filamentous fungi, including some clinically relevant species, such as Pseudallescheria boydii, Scedosporium aurantiacum, and Scedosporium apiospermum. Glucosylceramide (GlcCer), a conserved neutral glycosphingolipid, has been described as an important cell surface molecule playing a role in fungal morphological transition and pathogenesis. The present work aimed at the evaluation of GlcCer structures in S. aurantiacum and Pseudallescheria minutispora, a clinical and an environmental isolate, respectively, in order to determine their participation in fungal growth and host-pathogen interactions. Structural analysis by positive ion-mode ESI-MS (electrospray ionization mass spectrometer) revealed the presence of different ceramide moieties in GlcCer in these species. Monoclonal antibodies against Aspergillus fumigatus GlcCer could recognize S. aurantiacum and P. minutispora conidia, suggesting a conserved epitope in fungal GlcCer. In addition, these antibodies reduced fungal viability, enhanced conidia phagocytosis by macrophages, and decreased fungal survival inside phagocytic cells. Purified GlcCer from both species led to macrophage activation, increasing cell viability as well as nitric oxide and superoxide production in different proportions between the two species. These results evidenced some important properties of GlcCer from species of the Scedosporium/Lomentospora complex, as well as the effects of monoclonal anti-GlcCer antibodies on fungal cells and host-pathogen interaction. The differences between the two species regarding the observed biological properties suggest that variation in GlcCer structures and strain origin could interfere in the role of GlcCer in host-pathogen interaction.

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“…The basic structure of a sphingolipid is composed of a long-chain sphingoid base backbone linked to a fatty acid via an amide bond with the 2-amino group and to a polar head group at the C-1 position via an ester bond ( Figure 1) (Heung et al, 2006;Del Poeta et al, 2014). Sphingolipid biosynthesis begins in the endoplasmic reticulum (ER) and the genes and enzymes involved in sphingolipid biosynthesis have also been extensively studied (Dickson et al, 2006;Dickson, 2010;Fontaine, 2017;Fernandes et al, 2018, Zahumensky andMalinsky, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…The basic structure of a sphingolipid is composed of a long‐chain sphingoid base backbone linked to a fatty acid via an amide bond with the 2‐amino group and to a polar head group at the C‐1 position via an ester bond (Figure 1) (Heung et al ., 2006; Del Poeta et al ., 2014). Sphingolipid biosynthesis begins in the endoplasmic reticulum (ER) and the genes and enzymes involved in sphingolipid biosynthesis have also been extensively studied (Dickson et al ., 2006; Dickson, 2010; Fontaine, 2017; Fernandes et al ., 2018, Zahumensky and Malinsky, 2019). Although biosynthesis of sphingolipids is highly conserved between fungal cells and mammalian, some structural differences allow for sphingolipids to be considered a potential target for new antifungal drugs (Del Poeta et al ., 2014; Rollin‐Pinheiro et al ., 2016).…”

Section: Introductionmentioning

confidence: 99%

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

Song

Xiao

2020

Molecular Microbiology

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In recent years, the role of sphingolipids in pathogenic fungi, in terms of pathogenicity and resistance to azole drugs, has been a rapidly growing field. This review describes evidence about the roles of sphingolipids in azole resistance and fungal virulence. Sphingolipids can serve as signaling molecules that contribute to azole resistance through modulation of the expression of drug efflux pumps. They also contribute to azole resistance by participating in various microbial pathways such as the unfolded protein response (UPR), pH-responsive Rim pathway, and pleiotropic drug resistance (PDR) pathway. In addition, sphingolipid signaling and eisosomes also coordinately regulate sphingolipid biosynthesis in response to azole-induced membrane stress. Sphingolipids are important for fungal virulence, playing roles during growth in hosts under stressful conditions, maintenance of cell wall integrity, biofilm formation, and production of various virulence factors. Finally, we discuss the possibility of exploiting fungal sphingolipids for the development of new therapeutic strategies to treat infections caused by pathogenic fungi.

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Sphingolipids from the human fungal pathogen Aspergillus fumigatus

Cited by 19 publications

References 84 publications

Membrane Sphingolipids Regulate the Fitness and Antifungal Protein Susceptibility of Neurospora crassa

Membrane Sphingolipids Regulate the Fitness and Antifungal Protein Susceptibility of Neurospora crassa

Structural Differences Influence Biological Properties of Glucosylceramides from Clinical and Environmental Isolates of Scedosporium aurantiacum and Pseudallescheria minutispora

Sphingolipids: Regulators of azole drug resistance and fungal pathogenicity

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