Extensive functional redundancy in the regulation of <scp><i>C</i></scp><i>andida albicans</i> drug resistance and morphogenesis by lysine deacetylases <scp>H</scp>os2, <scp>H</scp>da1, <scp>R</scp>pd3 and <scp>R</scp>pd31

Li, Xinliu; Robbins, Nicole; O’Meara, Teresa R.; Cowen, Leah E.

doi:10.1111/mmi.13578

Cited by 35 publications

(39 citation statements)

References 67 publications

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“…Recent studies showed that Hsp90 acetylation has a profound impact on Hsp90 function. Li et al verified that the key acetylation sites on C. albicans Hsp90 are lysine 30 and 271 and substitutions at these residues phenocopy inhibition of Hsp90 (Li et al, 2017 ). Furthermore, HDAC inhibitors, such as trichostatin A (TSA) and MGCD290, a Hos2 HDAC inhibitor, have been shown to abrogate Hsp90-dependent azole resistance in C. albicans .…”

Section: Functions Of Hsps In C Albicansmentioning

confidence: 99%

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets

Gong

et al. 2017

Front. Cell. Infect. Microbiol.

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In recent decades, the incidence of invasive fungal infections has increased notably. Candida albicans (C. albicans), a common opportunistic fungal pathogen that dwells on human mucosal surfaces, can cause fungal infections, especially in immunocompromised and high-risk surgical patients. In addition, the wide use of antifungal agents has likely contributed to resistance of C. albicans to traditional antifungal drugs, increasing the difficulty of treatment. Thus, it is urgent to identify novel antifungal drugs to cope with C. albicans infections. Heat shock proteins (Hsps) exist in most organisms and are expressed in response to thermal stress. In C. albicans, Hsps control basic physiological activities or virulence via interaction with a variety of diverse regulators of cellular signaling pathways. Moreover, it has been demonstrated that Hsps confer drug resistance to C. albicans. Many studies have shown that disrupting the normal functions of C. albicans Hsps inhibits fungal growth or reverses the tolerance of C. albicans to traditional antifungal drugs. Here, we review known functions of the diverse Hsp family, Hsp-associated intracellular signaling pathways and potential antifungal targets based on these pathways in C. albicans. We hope this review will aid in revealing potential new roles of C. albicans Hsps in addition to canonical heat stress adaptions and provide more insight into identifying potential novel antifungal targets.

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Section: Functions Of Hsps In C Albicansmentioning

confidence: 99%

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets

Gong

et al. 2017

Front. Cell. Infect. Microbiol.

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“…Filamentation in response to Hsp90 inhibition is dependent on most components of the cAMP-PKA pathway[ 17 ], interactions with the cell cycle kinase Cdc28[ 19 ], and signaling through the cyclin Pcl1, cyclin-dependent kinase Pho85 and transcription factor Hms1[ 20 ]. Further, Hsp90 function is regulated by complex interactions with co-chaperones that regulate its ATPase activity and mediate interactions with client proteins, and by post-translational modifications such as phosphorylation and acetylation[ 15 , 21 ], which can have profound effects on cellular responses to thermal stress and on morphogenesis[ 16 , 22 ].…”

Section: Introductionmentioning

confidence: 99%

Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space

Veri

Miao²,

Shapiro

et al. 2018

PLoS Genet

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The capacity to respond to temperature fluctuations is critical for microorganisms to survive within mammalian hosts, and temperature modulates virulence traits of diverse pathogens. One key temperature-dependent virulence trait of the fungal pathogen Candida albicans is its ability to transition from yeast to filamentous growth, which is induced by environmental cues at host physiological temperature. A key regulator of temperature-dependent morphogenesis is the molecular chaperone Hsp90, which has complex functional relationships with the transcription factor Hsf1. Although Hsf1 controls global transcriptional remodeling in response to heat shock, its impact on morphogenesis remains unknown. Here, we establish an intriguing paradigm whereby overexpression or depletion of C. albicans HSF1 induces morphogenesis in the absence of external cues. HSF1 depletion compromises Hsp90 function, thereby driving filamentation. HSF1 overexpression does not impact Hsp90 function, but rather induces a dose-dependent expansion of Hsf1 direct targets that drives overexpression of positive regulators of filamentation, including Brg1 and Ume6, thereby bypassing the requirement for elevated temperature during morphogenesis. This work provides new insight into Hsf1-mediated environmentally contingent transcriptional control, implicates Hsf1 in regulation of a key virulence trait, and highlights fascinating biology whereby either overexpression or depletion of a single cellular regulator induces a profound developmental transition.

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“…Similarly, in C. albicans , CK2 phosphorylates Hsp90, and compromised CK2 function reduces the functional capacity of Hsp90 [38]. Hsp90 is also regulated by acetylation on numerous lysine residues [54-57]. In S. cerevisiae , Hsp90 is acetylated on lysine 27 and 270, as well as on other residues that remain enigmatic [56].…”

Section: Hsp90 Regulationmentioning

confidence: 99%

“…In S. cerevisiae , Hsp90 is acetylated on lysine 27 and 270, as well as on other residues that remain enigmatic [56]. In C. albicans , lysine 30 and 271 are the analogous critical acetylation sites, and are important for Hsp90 function [57]. Hsp90 acetylation also regulates drug resistance and virulence in the fungal pathogen Aspergillus fumigatus [58,59].…”

Section: Hsp90 Regulationmentioning

confidence: 99%

“…In S. cerevisiae , the lysine deacetylases (KDACs) important for regulating Hsp90 are Hda1 and Rpd3 [56]. Intriguingly, in C. albicans , there is a high level of functional redundancy among KDACs, with Hos2, Hda1, Rpd3, and Rpd31 mediating azole resistance and morphogenesis [57]. Multiple members of the Hos2 complex, including HOS2 and SNT1 , are genetic interactors with Hsp90 under diverse environmental stresses, implicating this complex in regulation of Hsp90 function [38,39].…”

Section: Hsp90 Regulationmentioning

confidence: 99%

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The Hsp90 Chaperone Network Modulates Candida Virulence Traits

O’Meara

Robbins

Cowen

2017

Trends in Microbiology

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Hsp90 is a conserved molecular chaperone that facilitates the folding and function of client proteins. Hsp90 function is dynamically regulated by interactions with co-chaperones and by post-translational modifications. In the fungal pathogen Candida albicans, Hsp90 enables drug resistance and virulence by stabilizing diverse signal transducers. Here, we review studies that have unveiled regulators of Hsp90 function, as well as downstream effectors that govern the key virulence traits of morphogenesis and drug resistance. We highlight recent work mapping the Hsp90 genetic network in C. albicans under diverse environmental conditions, and how these interactions provide insight into circuitry important for drug resistance, morphogenesis, and virulence. Ultimately, elucidating the Hsp90 chaperone network will aid in the development of therapeutics to treat fungal disease.

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Extensive functional redundancy in the regulation of Candida albicans drug resistance and morphogenesis by lysine deacetylases Hos2, Hda1, Rpd3 and Rpd31

Cited by 35 publications

References 67 publications

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets

Candida albicans Heat Shock Proteins and Hsps-Associated Signaling Pathways as Potential Antifungal Targets

Tuning Hsf1 levels drives distinct fungal morphogenetic programs with depletion impairing Hsp90 function and overexpression expanding the target space

The Hsp90 Chaperone Network Modulates Candida Virulence Traits

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