Identification of a key lysine residue in heat shock protein 90 required for azole and echinocandin resistance in Aspergillus fumigatus.

Details

Serval ID
serval:BIB_6AE3DA5CFAAA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Identification of a key lysine residue in heat shock protein 90 required for azole and echinocandin resistance in Aspergillus fumigatus.
Journal
Antimicrobial Agents and Chemotherapy
Author(s)
Lamoth F., Juvvadi P.R., Soderblom E.J., Moseley M.A., Asfaw Y.G., Steinbach W.J.
ISSN
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
2014
Peer-reviewed
Oui
Volume
58
Number
4
Pages
1889-1896
Language
english
Notes
Publication types: Journal Article
Abstract
Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced Aspergillus fumigatus virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in A. fumigatus. Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylation-mimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in Candida albicans, the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against A. fumigatus and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in A. fumigatus and that deacetylase inhibition may represent an adjunctive anti-Aspergillus strategy.
Pubmed
Web of science
Open Access
Yes
Create date
01/05/2014 17:44
Last modification date
20/08/2019 14:25
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