Glycosylphosphatidylinositol (GPI) anchor is required in <i>Aspergillus fumigatus</i> for morphogenesis and virulence

Li, Hong; Zhou, Hui; Luo, Yuanming; Ouyang, Hongwei; Hu, Hai; Jin, Cheng

doi:10.1111/j.1365-2958.2007.05709.x

Cited by 71 publications

(56 citation statements)

References 56 publications

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“…The presence of these genes in our data set was not expected, as although GPI anchors are required for hyphal and conidial wall stability, they are apparently dispensable for viability in A. fumigatus (31). It is clear from a study by Li et al (31) that GPI mutants exhibit many growth defects.…”

Section: Discussionmentioning

confidence: 66%

“…The Eisai R&D Management Co. Ltd. has recently published evidence that small molecules can target this process in C. albicans, leading to a positive therapeutic outcome in a mammalian infection model (34). Interestingly and apparently in contradiction to the dispensability of GPI biosynthesis described by Li et al (31), many of the compounds detailed in this patent application also possessed anti-Aspergillus activity.…”

Section: Discussionmentioning

confidence: 72%

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The Transposon impala Is Activated by Low Temperatures: Use of a Controlled Transposition System To Identify Genes Critical for Viability of Aspergillus fumigatus

Carr¹,

Tuckwell²,

Hey³

et al. 2010

Eukaryot Cell

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Genes that are essential for viability represent potential targets for the development of anti-infective agents. However, relatively few have been determined in the filamentous fungal pathogen Aspergillus fumigatus. A novel solution employing parasexual genetics coupled with transposon mutagenesis using the Fusarium oxysporum transposon impala had previously enabled the identification of 20 essential genes from A. fumigatus; however, further use of this system required a better understanding of the mode of action of the transposon itself. Examination of a range of conditions indicated that impala is activated by prolonged exposure to low temperatures. This newly identified property was then harnessed to identify 96 loci that are critical for viability in A. fumigatus, including genes required for RNA metabolism, organelle organization, protein transport, ribosome biogenesis, and transcription, as well as a number of noncoding RNAs. A number of these genes represent potential targets for much-needed novel antifungal drugs.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 72%

The Transposon impala Is Activated by Low Temperatures: Use of a Controlled Transposition System To Identify Genes Critical for Viability of Aspergillus fumigatus

Carr¹,

Tuckwell²,

Hey³

et al. 2010

Eukaryot Cell

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“…1 and 2). Formations of intrahyphal hyphae or double-layered cell walls were observed in some deletion mutants of the class V or VI chitin synthase-encoding genes and the genes involved in the biosynthesis of the glycosylphosphatidylinositol anchor that connects proteins working for cell wall structure maintenance (4,14,25,26,32,44). In N. crassa and Aspergillus oryzae, it has been reported that new hyphae are generated from septa when Woronin body plugged a septal pore (19,27,45).…”

Section: Discussionmentioning

confidence: 99%

Class III Chitin Synthase ChsB of Aspergillus nidulans Localizes at the Sites of Polarized Cell Wall Synthesis and Is Required for Conidial Development

Fukuda¹,

Yamada²,

Deoka³

et al. 2009

Eukaryot Cell

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Class III chitin synthases play important roles in tip growth and conidiation in many filamentous fungi. However, little is known about their functions in those processes. To address these issues, we characterized the deletion mutant of a class III chitin synthase-encoding gene of Aspergillus nidulans, chsB, and investigated ChsB localization in the hyphae and conidiophores. Multilayered cell walls and intrahyphal hyphae were observed in the hyphae of the chsB deletion mutant, and wavy septa were also occasionally observed. ChsB tagged with FLAG or enhanced green fluorescent protein (EGFP) localized mainly at the tips of germ tubes, hyphal tips, and forming septa during hyphal growth. EGFP-ChsB predominantly localized at polarized growth sites and between vesicles and metulae, between metulae and phialides, and between phalides and conidia in asexual development. These results strongly suggest that ChsB functions in the formation of normal cell walls of hyphae, as well as in conidiophore and conidia development in A. nidulans.Chitin, a polymer of ␤-1,4-linked N-acetylglucosmine, is one of the major structural components of the fungal cell wall. Its metabolism, including synthesis, degradation, assembly, and cross-linking to other cell wall components, is thought to be very important for many fungi (5,22,24,36,45). Fungal chitin synthases have been classified into seven groups, classes I to VII, depending on the structures of their conserved regions (6). The genes encoding the synthases belonging to classes III, V, VI, and VII are only found in fungi with high chitin contents in their cell walls. We have identified six chitin synthase genes from Aspergillus nidulans and designated them chsA, chsB, chsC, chsD, csmA, and csmB; these gene products belong to classes II, III, I, IV, V, and VI, respectively (9,13,30,31,44,52). The chsB deletion mutant grew very slowly and formed small colonies with highly branched hyphae, suggesting its important role in hyphal tip growth (3, 52). Repression of chsB expression in the deletion mutant of chsA, chsC, or chsD exaggerated the defects in the formation of aerial hyphae, the production of cell mass, or the growth under high-osmolarity conditions, respectively, compared to each single mutant. These results indicate that chsB functions at various stages of development (15, 16).The deletion of class III chitin synthase-encoding genes leads to severe defects in most of the filamentous fungi thus far investigated. However, their detailed functions are currently unknown. In Neurospora crassa, inactivation of the gene encoding Chs-1, a class III chitin synthase with 63% identity to A. nidulans ChsB, leads to slow growth, aberrant hyphal morphology, and a decrease in chitin synthase activity. The mutant of chs-1 became sensitive to Nikkomycin Z, a chitin synthase inhibitor (53). In Aspergillus fumigatus, two genes encoding class III chitin synthases, chsC and chsG, have been identified. Their gene products showed 66 and 89% identity, respectively, to A. nidulans ChsB. The chsG deletio...

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“…In addition to the importance of GPI-anchored proteins, GPI anchor biosynthesis plays a critical role in morphogenesis. In A. fumigatus, the GPI-N-acetylglucosaminyltransferase complex catalyzes GPI biosynthesis via the PigA complex (324). The deletion of pigA leads to an inhibition of GPI anchor synthesis and causes severe cell wall defects as well as abnormal hyphal growth and abnormal conidiation (324).…”

Section: Major Morphogenetic Signaling Cascadesmentioning

confidence: 99%

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Shapiro

Robbins

Cowen

2011

Microbiol Mol Biol Rev

489

547

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SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

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Glycosylphosphatidylinositol (GPI) anchor is required in Aspergillus fumigatus for morphogenesis and virulence

Cited by 71 publications

References 56 publications

The Transposon impala Is Activated by Low Temperatures: Use of a Controlled Transposition System To Identify Genes Critical for Viability of Aspergillus fumigatus

The Transposon impala Is Activated by Low Temperatures: Use of a Controlled Transposition System To Identify Genes Critical for Viability of Aspergillus fumigatus

Class III Chitin Synthase ChsB of Aspergillus nidulans Localizes at the Sites of Polarized Cell Wall Synthesis and Is Required for Conidial Development

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

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