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Hsp90 Orchestrates Temperature-Dependent Candida albicans Morphogenesis via Ras1-PKA Signaling
Open accessAbstract
Background Hsp90 is an environmentally contingent molecular chaperone that influences the form and function of diverse regulators of cellular signaling. Hsp90 potentiates the evolution of fungal drug resistance by enabling crucial cellular stress responses. Here we demonstrate that in the leading fungal pathogen of humans, Candida albicans, Hsp90 governs cellular circuitry required not only for drug resistance but also for the key morphogenetic transition from yeast to filamentous growth that is crucial for virulence. This transition is normally regulated by environmental cues, such as exposure to serum, that are contingent upon elevated temperature to induce morphogenesis. The basis for this temperature dependence has remained enigmatic.Results We show that compromising Hsp90 function pharmacologically or genetically induces a transition from yeast to filamentous growth in the absence of external cues. Elevated temperature relieves Hsp90-mediated repression of the morphogenetic program. Hsp90 regulates morphogenetic circuitry by repressing Ras1-PKA signaling. Modest Hsp90 compromise enhances the phenotypic effects of activated Ras1 signaling whereas deletion of positive regulators of the Ras1-PKA cascade blocks the morphogenetic response to Hsp90 inhibition. Consistent with the requirement for morphogenetic flexibility for virulence, depletion of C. albicans Hsp90 attenuates virulence in a murine model of systemic disease.Conclusions Hsp90 governs the integration of environmental cues with cellular signaling to orchestrate fungal morphogenesis and virulence, suggesting new therapeutic strategies for life-threatening infectious disease. Hsp90's capacity to govern a key developmental program in response to temperature change provides a new mechanism that complements the elegant repertoire that organisms utilize to sense temperature.
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“Under these conditions, the MAL2p-HSP90/hsp90Δ strain has reduced growth rate and reaches approximately half the stationary phase cell density as a wild-type strain [40].”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Our previous work established that genetic reduction of Hsp90 levels enhances the efficacy of fluconazole in a murine model of disseminated C. albicans infection [22] and that further genetic depletion of C. albicans Hsp90 results in complete clearance of an infection in the murine model [40].”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [40]
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In the citing paper
“As expected, exposure of cells containing the UTR2-lacZ reporter to calcium chloride resulted in activation of calcineurin relative to the untreated control (P<0.001, ANOVA, Bonferroni's Multiple Comparison Test Figure 4C).”
From Hsp90 Governs Echinocandin Resistance in the Pathogenic Yeast Candida albicans via Calcineurin (2009) · cites this paper as [40]
In the citing paper
“Hsp90 also modulates key virulence traits in C. albicans, such as the ability to undergo morphogenesis, and in animal models, genetic compromise of Hsp90 function leads to clearance of otherwise lethal Candida or Aspergillus infections (Cowen et al. 2009; Shapiro et al. 2009).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Shapiro et al. 2009
In the citing paper
“Hsp90 functions as a signaling hub, stabilizing various signal transducers that modulate key fungal virulence phenotypes (Cowen and Lindquist 2005; Shapiro et al. 2009; O’Meara et al. 2019; Hossain et al. 2020).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Shapiro et al. 2009
In the citing paper
“In C. albicans, Hsp90 modulates cellular responses to antifungals by stabilizing components of the Pkc1-MAPK and calcineurin stress-response pathways (Cowen and Lindquist 2005; Cowen et al. 2009; Shapiro et al. 2009).”
From Genetic analysis of Hsp90 function in Cryptococcus neoformans highlights key roles in stress tolerance and virulence (2022) · cites this paper as Shapiro et al. 2009
In the citing paper
“At elevated temperatures (circa 37°C) this Hsp90 repression is relieved, leading to filamentation.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [115]
In the citing paper
“Hsp90 regulates morphogenesis in C. albicans by repressing Ras1-PKA signalling at relatively low temperatures115.”
From Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs (2012) · cites this paper as [115]
In the citing paper
“The molecular chaperone Hsp90 regulates morphogenesis of the leading human fungal pathogen Candida albicans.”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans (2012) · cites this paper as Shapiro et al., 2009
In the citing paper
“Hsp90 is a key temperature sensor governing morphogenesis, given that reduction of Hsp90 function bypasses the requirement for elevated temperature for cues such as serum to induce filamentous growth and that Hsp90 function is partially compromised in conditions that induce hyphal morphogenesis (Shapiro et al., 2009).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans (2012) · cites this paper as Shapiro et al., 2009
In the citing paper
“Recently the molecular chaperone heat shock protein 90 (Hsp90) has been implicated as an important regulator of the temperature-dependent switch between yeast and filamentous growth in C. albicans (Shapiro et al., 2009).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans (2012) · cites this paper as Shapiro et al., 2009
In the citing paper
“Depletion of Hsp90 also leads to clearance of kidney fungal burden in a mouse model of candidiasis (Shapiro et al., 2009).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans (2012) · cites this paper as Shapiro et al., 2009
In the citing paper
“Hsp90 is an important molecular chaperone that governs key virulence traits in C. albicans (Cowen and Lindquist, 2005; Shapiro et al., 2009; Singh et al., 2009).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans (2012) · cites this paper as Shapiro et al., 2009
In the citing paper
“Hsp90 regulates temperature-dependent morphogenesis by exerting a repressive effect on Ras1-PKA signaling, which is alleviated upon temperature elevation (Shapiro et al., 2009).”
From Cdc28 provides a molecular link between Hsp90, morphogenesis, and cell cycle progression in Candida albicans (2012) · cites this paper as Shapiro et al., 2009
In the citing paper
“Hsp90, an essential molecular chaperone [1,3,5,6], has been shown to govern various aspects of C. albicans pathogenicity determinants including morphological yeast to hyphal transition [7], emergence of drug resistance [8–10] and biofilm formation [11].”
From Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans (2017) · cites this paper as [7]
In the citing paper
“Interestingly Hsp90 has been shown to be the regulator of this switch by repressing the Ras1-PKA signaling pathway [7].”
From Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans (2017) · cites this paper as [7]
In the citing paper
“In addition to its role in enabling the emergence and maintenance of azole resistance, Hsp90 governs temperature-dependent morphogenesis in C. albicans (19).”
From Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance (2019) · cites this paper as [19]
In the citing paper
“Hsp90 represses filamentous growth in C. albicans such that compromising Hsp90 function induces the yeast-to-filament transition by relieving repression on Ras1-protein kinase A (PKA) signaling (19).”
From Genetic Analysis of Candida auris Implicates Hsp90 in Morphogenesis and Azole Tolerance and Cdr1 in Azole Resistance (2019) · cites this paper as [19]
In the citing paper
“Depletion of Hsp90 also induces filamentation by relieving Hsp90-mediated repression of the cAMP-PKA signaling pathway (181).”
From Candida albicans Biofilms and Human Disease (2015) · cites this paper as [181]
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Self-citation
Metadata
- Authors
- Shapiro, R. S., Uppuluri, P., Zaas, A. K., Collins, C., Senn, H., Perfect, J. R., Heitman, J., & Cowen, L. E.
- Affiliations
- University of Toronto (CA)
- Duke Medical Center (US)
- Corresponding author
- Cowen, Leah E.
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 19
- Issue
- 8
- Pages
- 621-629
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC2735497
- OpenAlex
- W1967864456
- Cited by
- 311
- References
- 50
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 14 · 2023: 11 · 2022: 10 · 2021: 25 · 2020: 20 · 2019: 18 · 2018: 23 · 2017: 15 · 2016: 28 · 2015: 19 · 2014: 16 · 2013: 18 · 2012: 24
- FWCI
- 9.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1604 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Current Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (AI 73896, R56AI028388, AI28388, R01AI073896, R01AI028388, AI-50438, R01AI050438, K08AI065837)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- HSP90, Candida albicans, fungal morphogenesis, yeast-to-hypha transition, temperature dependence, fungal virulence, drug resistance, molecular chaperones, antifungal therapy
- MeSH terms
- Animals, Candida albicans, Candidiasis, Fungal Proteins, Humans, Isoenzymes, Morphogenesis, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, ras Proteins, HSP90 Heat-Shock Proteins, GTPase-Activating Proteins, Hyphae, Mice, Quorum Sensing, Cyclic Nucleotide Phosphodiesterases, Type 1, Cyclic Nucleotide Phosphodiesterases, Type 2
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