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

摘要: ABSTRACT Aspergillus fumigatus is the primary etiologic agent of invasive aspergillosis (IA), a major cause death among immunosuppressed patients. Echinocandins (e.g., caspofungin) are increasingly used as second-line therapy for IA, but their activity only fungistatic. Heat shock protein 90 (Hsp90) was previously shown to trigger tolerance caspofungin and paradoxical effect (i.e., decreased efficacy at higher concentrations). Here, we demonstrate key role another molecular chaperone, Hsp70, in governing stress response via Hsp90 cochaperone Hop/Sti1 (StiA A. fumigatus). Mutation StiA-interacting domain Hsp70 (C-terminal EELD motif) impaired thermal adaptation with loss effect. Impaired function increased susceptibility were also observed following pharmacologic inhibition C-terminal by pifithrin-μ or after stiA deletion, further supporting links StiA, tolerance. StiA not required physical interaction between had distinct roles regulation heat responses. In conclusion, this study deciphering functional interactions Hsp70-StiA-Hsp90 complex provided new insights into mechanisms revealed motif which can be targeted specific inhibitors, such pifithrin-μ, enhance antifungal against fumigatus.