Document Detail

Heat shock protein 90 is required for conidiation and cell wall integrity in Aspergillus fumigatus.
MedLine Citation:
PMID:  22822234     Owner:  NLM     Status:  MEDLINE    
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.
Frédéric Lamoth; Praveen R Juvvadi; Jarrod R Fortwendel; William J Steinbach
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-20
Journal Detail:
Title:  Eukaryotic cell     Volume:  11     ISSN:  1535-9786     ISO Abbreviation:  Eukaryotic Cell     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-29     Completed Date:  2013-04-08     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  101130731     Medline TA:  Eukaryot Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1324-32     Citation Subset:  IM    
Division of Pediatric Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
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MeSH Terms
Aspergillus fumigatus / genetics,  growth & development,  metabolism*
Benzoquinones / pharmacology
Cell Wall / drug effects,  genetics,  metabolism*
Cytosol / metabolism
Echinocandins / pharmacology
Fungal Proteins / antagonists & inhibitors,  genetics,  metabolism*
Gene Deletion
Gene Expression Regulation, Fungal
Green Fluorescent Proteins / metabolism
HSP90 Heat-Shock Proteins / antagonists & inhibitors,  genetics,  metabolism*
Hyphae / drug effects
Lactams, Macrocyclic / pharmacology
Microbial Viability
Promoter Regions, Genetic
Spores, Fungal / genetics,  growth & development*,  metabolism
Stress, Physiological
Tacrolimus / pharmacology
Transcription Factors / genetics,  metabolism
Transcription, Genetic
beta-Glucans / metabolism
Grant Support
1R56AI077648-01A2/AI/NIAID NIH HHS; 5T32-AI052080/AI/NIAID NIH HHS
Reg. No./Substance:
0/Benzoquinones; 0/Echinocandins; 0/Fungal Proteins; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 0/Transcription Factors; 0/beta-Glucans; 109581-93-3/Tacrolimus; 147336-22-9/Green Fluorescent Proteins; 9051-97-2/beta-1,3-glucan; F0XDI6ZL63/caspofungin; Z3K3VJ16KU/geldanamycin

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