The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance.

dc.contributor.author

Shapiro, Rebecca S

dc.contributor.author

Zaas, Aimee K

dc.contributor.author

Betancourt-Quiroz, Marisol

dc.contributor.author

Perfect, John R

dc.contributor.author

Cowen, Leah E

dc.contributor.editor

Poeta, Maurizio Del

dc.coverage.spatial

United States

dc.date.accessioned

2017-08-28T15:32:01Z

dc.date.available

2017-08-28T15:32:01Z

dc.date.issued

2012

dc.description.abstract

The molecular chaperone Hsp90 orchestrates regulatory circuitry governing fungal morphogenesis, biofilm development, drug resistance, and virulence. Hsp90 functions in concert with co-chaperones to regulate stability and activation of client proteins, many of which are signal transducers. Here, we characterize the first Hsp90 co-chaperone in the leading human fungal pathogen, Candida albicans. We demonstrate that Sgt1 physically interacts with Hsp90, and that it governs C. albicans morphogenesis and drug resistance. Genetic depletion of Sgt1 phenocopies depletion of Hsp90, inducing yeast to filament morphogenesis and invasive growth. Sgt1 governs these traits by bridging two morphogenetic regulators: Hsp90 and the adenylyl cyclase of the cAMP-PKA signaling cascade, Cyr1. Sgt1 physically interacts with Cyr1, and depletion of either Sgt1 or Hsp90 activates cAMP-PKA signaling, revealing the elusive link between Hsp90 and the PKA signaling cascade. Sgt1 also mediates tolerance and resistance to the two most widely deployed classes of antifungal drugs, azoles and echinocandins. Depletion of Sgt1 abrogates basal tolerance and acquired resistance to azoles, which target the cell membrane. Depletion of Sgt1 also abrogates tolerance and resistance to echinocandins, which target the cell wall, and renders echinocandins fungicidal. Though Sgt1 and Hsp90 have a conserved impact on drug resistance, the underlying mechanisms are distinct. Depletion of Hsp90 destabilizes the client protein calcineurin, thereby blocking crucial responses to drug-induced stress; in contrast, depletion of Sgt1 does not destabilize calcineurin, but blocks calcineurin activation in response to drug-induced stress. Sgt1 influences not only morphogenesis and drug resistance, but also virulence, as genetic depletion of C. albicans Sgt1 leads to reduced kidney fungal burden in a murine model of systemic infection. Thus, our characterization of the first Hsp90 co-chaperone in a fungal pathogen establishes C. albicans Sgt1 as a global regulator of morphogenesis and drug resistance, providing a new target for treatment of life-threatening fungal infections.

dc.identifier

https://www.ncbi.nlm.nih.gov/pubmed/22970302

dc.identifier

PONE-D-12-18759

dc.identifier.eissn

1932-6203

dc.identifier.uri

https://hdl.handle.net/10161/15369

dc.language

eng

dc.publisher

Public Library of Science (PLoS)

dc.relation.ispartof

PLoS One

dc.relation.isversionof

10.1371/journal.pone.0044734

dc.subject

Adenylyl Cyclases

dc.subject

Antifungal Agents

dc.subject

Azoles

dc.subject

Candida albicans

dc.subject

Cyclic AMP

dc.subject

Cyclic AMP-Dependent Protein Kinases

dc.subject

Drug Resistance, Fungal

dc.subject

HSP90 Heat-Shock Proteins

dc.subject

Morphogenesis

dc.subject

Protein Binding

dc.subject

Signal Transduction

dc.title

The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance.

dc.type

Journal article

duke.contributor.orcid

Perfect, John R|0000-0002-6606-9460|0000-0003-3465-5518

pubs.author-url

https://www.ncbi.nlm.nih.gov/pubmed/22970302

pubs.begin-page

e44734

pubs.issue

9

pubs.organisational-group

Basic Science Departments

pubs.organisational-group

Clinical Science Departments

pubs.organisational-group

Duke

pubs.organisational-group

Medicine

pubs.organisational-group

Medicine, Infectious Diseases

pubs.organisational-group

Molecular Genetics and Microbiology

pubs.organisational-group

School of Medicine

pubs.publication-status

Published

pubs.volume

7

Files

Original bundle

Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
The Hsp90 co-chaperone Sgt1 governs Candida albicans morphogenesis and drug resistance.pdf
Size:
1.02 MB
Format:
Adobe Portable Document Format
Description:
Accepted version