Hsp70 and the Cochaperone StiA (Hop) Orchestrate Hsp90-Mediated Caspofungin Tolerance in Aspergillus fumigatus.

Details

Serval ID
serval:BIB_4823976FAAB7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Hsp70 and the Cochaperone StiA (Hop) Orchestrate Hsp90-Mediated Caspofungin Tolerance in Aspergillus fumigatus.
Journal
Antimicrobial Agents and Chemotherapy
Author(s)
Lamoth F., Juvvadi P.R., Soderblom E.J., Moseley M.A., Steinbach W.J.
ISSN
1098-6596 (Electronic)
ISSN-L
0066-4804
Publication state
Published
Issued date
2015
Peer-reviewed
Oui
Volume
59
Number
8
Pages
4727-4733
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
Publication Status: ppublish
Abstract
Aspergillus fumigatus is the primary etiologic agent of invasive aspergillosis (IA), a major cause of death among immunosuppressed patients. Echinocandins (e.g., caspofungin) are increasingly used as second-line therapy for IA, but their activity is only fungistatic. Heat shock protein 90 (Hsp90) was previously shown to trigger tolerance to caspofungin and the paradoxical effect (i.e., decreased efficacy of caspofungin at higher concentrations). Here, we demonstrate the key role of another molecular chaperone, Hsp70, in governing the stress response to caspofungin via Hsp90 and their cochaperone Hop/Sti1 (StiA in A. fumigatus). Mutation of the StiA-interacting domain of Hsp70 (C-terminal EELD motif) impaired thermal adaptation and caspofungin tolerance with loss of the caspofungin paradoxical effect. Impaired Hsp90 function and increased susceptibility to caspofungin were also observed following pharmacologic inhibition of the C-terminal domain of Hsp70 by pifithrin-μ or after stiA deletion, further supporting the links among Hsp70, StiA, and Hsp90 in governing caspofungin tolerance. StiA was not required for the physical interaction between Hsp70 and Hsp90 but had distinct roles in the regulation of their function in caspofungin and heat stress responses. In conclusion, this study deciphering the physical and functional interactions of the Hsp70-StiA-Hsp90 complex provided new insights into the mechanisms of tolerance to caspofungin in A. fumigatus and revealed a key C-terminal motif of Hsp70, which can be targeted by specific inhibitors, such as pifithrin-μ, to enhance the antifungal activity of caspofungin against A. fumigatus.
Keywords
Antifungal Agents/pharmacology, Aspergillus fumigatus/drug effects, Aspergillus fumigatus/metabolism, Echinocandins/pharmacology, Fungal Proteins/metabolism, HSP70 Heat-Shock Proteins/metabolism, HSP90 Heat-Shock Proteins/metabolism, Heat-Shock Response/drug effects, Humans, Molecular Chaperones/metabolism, Protein Binding, Protein Structure, Tertiary
Pubmed
Web of science
Open Access
Yes
Create date
17/11/2015 18:39
Last modification date
20/08/2019 14:54
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