The DOI matches its Crossref record; 41 of the 42 references it cites were found in a registry or an index.
Heat Shock Protein 90 Is Required for Conidiation and Cell Wall Integrity in Aspergillus fumigatus
Open accessAbstract
Heat shock protein 90 (Hsp90) is a eukaryotic molecular chaperone. Its involvement in the resistance of Candida albicans to azole and echinocandin antifungals is well established. However, little is known about Hsp90's function in the filamentous fungal pathogen Aspergillus fumigatus . We investigated the role of Hsp90 in A. fumigatus by genetic repression and examined its cellular localization under various stress conditions. Failure to generate a deletion strain of hsp90 suggested that it is essential. Genetic repression of Hsp90 was achieved by an inducible nitrogen-dependent promoter ( pniiA -Hsp90) and led to decreased spore viability, decreased hyphal growth, and severe defects in germination and conidiation concomitant with the downregulation of the conidiation-specific transcription factors brlA , wetA , and abaA . Hsp90 repression potentiated the effect of cell wall inhibitors affecting the β-glucan structure of the cell wall (caspofungin, Congo red) and of the calcineurin inhibitor FK506, supporting a role in regulating cell wall integrity pathways. Moreover, compromising Hsp90 abolished the paradoxical effect of caspofungin. Pharmacological inhibition of Hsp90 by geldanamycin and its derivatives (17-AAG and 17-DMAG) resulted in similar effects. C-terminal green fluorescent protein (GFP) tagging of Hsp90 revealed mainly cytosolic distribution under standard growth conditions. However, treatment with caspofungin resulted in Hsp90 accumulation at the cell wall and at sites of septum formation, further highlighting its role in cell wall stress compensatory mechanisms. Targeting Hsp90 with fungal-specific inhibitors to cripple stress response compensatory pathways represents an attractive new antifungal strategy.
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In the citing paper
“Calcineurin inhibitors (FK506 and cyclosporine) and Hsp90 inhibitors (geldanamycin, 17-allylamino-17-demethoxygeldanamycin [17-AAG], and 17-demethylaminoethylamino-17-demethoxygeldanamycin [17-DMAG]) are active against A. fumigatus and potentiate the effect of caspofungin (6–8)”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [7]
In the citing paper
“Compromising Hsp90-mediated stress responses by genetic modifications of the hsp90 promoter also potentiated the effect of caspofungin and abolished the paradoxical effect of this drug (7, 12).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [7]
In the citing paper
“These phenotypic characteristics were similar to those obtained after genetic repression of Hsp90 (7, 12).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [7]
In the citing paper
“Interestingly, deletion of rpdA (a class 1 KDAC), whose contribution to KDAC activity is less important, was lethal in A. nidulans, and its repression resulted in growth and conidiation defects that were comparable to the phenotypic consequences of Hsp90 repression in our previous works (7, 12, 41).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [7]
In the citing paper
“Differences regarding susceptibility to azoles were also observed following Hsp90 repression in A. fumigatus and C. albicans (6, 7, 10, 12).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [7]
In the citing paper
“Interestingly, deletion of rpdA (a class 1 KDAC), whose contribution to KDAC activity is less important, was lethal in A. nidulans, and its repression resulted in growth and conidiation defects that were comparable to the phenotypic consequences of Hsp90 repression in our previous works (7, 12, 41).”
From Identification of a Key Lysine Residue in Heat Shock Protein 90 Required for Azole and Echinocandin Resistance in Aspergillus fumigatus (2014) · cites this paper as [7]
In the citing paper
“In Aspergillus fumigatus, the role of Hsp90 in drug resistance [16], conidiation and maintenance of cell wall integrity has been well established [17].”
From Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans (2017) · cites this paper as [17]
In the citing paper
“Supporting these observations, there was down-regulation of the conidiation-specific transcription factors brlA, wetA under Hsp90 repression (Lamoth et al., 2012).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Lamoth et al., 2012
In the citing paper
“Genetic or pharmacologic inhibition of Hsp90 or calcineurin did not (or only modestly) impact azole susceptibility (Lamoth et al., 2012; Lamoth et al., 2013a; Steinbach et al., 2004a).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Lamoth et al., 2012
In the citing paper
“Subcellular localization analysis of A. fumigatus Hsp90 using an EGFP-tagged strain showed that Hsp90 was abundantly distributed within the cytosol under standard growth conditions and moved to the nucleus under heat stress or to the cell wall, septa and hyphal tips in response to the cell wall stress induced by caspofungin (Lamoth et al., 2012).”
From Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis (2014) · cites this paper as Lamoth et al., 2012
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Antifungal Drug Resistance: Molecular Mechanisms in Candida albicans and Beyond
Lee, Y., Puumala, E., Robbins, N., & Cowen, L. E. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00199 · Cited by 801
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Antifungal Drugs: The Current Armamentarium and Development of New Agents
Robbins, N., Wright, G. D., & Cowen, L. E. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.funk-0002-2016 · Cited by 271
Role of Heat-Shock Proteins in Cellular Function and in the Biology of Fungi
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Metadata
- Authors
- Lamoth, F., Juvvadi, P. R., Fortwendel, J. R., & Steinbach, W. J.
- Affiliations
- Duke Medical Center (US)
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2012-11
- Volume
- 11
- Issue
- 11
- Pages
- 1324-1332
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC3486032
- OpenAlex
- W2106567443
- Semantic Scholar
- eb6f3834aabdc76c9098700ed11d9c6f343b2fea
- Cited by
- 136
- References
- 42
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 7 · 2023: 5 · 2022: 11 · 2021: 8 · 2020: 12 · 2019: 10 · 2018: 9 · 2017: 11 · 2016: 19 · 2015: 17 · 2014: 10 · 2013: 5 · 2012: 2
- FWCI
- 4.37
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (134303)
- National Institute of Allergy and Infectious Diseases (R56AI077648, T32AI052080)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- HSP90, Aspergillus fumigatus, conidiation, cell wall integrity, molecular chaperones, brlA, weta, abaA, caspofungin, Congo red, FK506, geldanamycin, 17-AAG, 17-DMAG, hyphal growth, spore viability, septum formation, antifungal drug targets, fungal pathogens
- MeSH terms
- Caspofungin, Aspergillus fumigatus, Cell Wall, Cytosol, Fungal Proteins, Promoter Regions, Genetic, Spores, Fungal, Stress, Physiological, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Fungal, Benzoquinones, Tacrolimus, Gene Deletion, HSP90 Heat-Shock Proteins, Hyphae, Lactams, Macrocyclic, beta-Glucans, Green Fluorescent Proteins, Microbial Viability, Echinocandins, Lipopeptides
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