Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs

Leach, Michelle; Klipp, Edda; Cowen, Leah E.; Brown, Alistair J. P.

doi:10.1038/nrmicro2875

Cited by 87 publications

(112 citation statements)

References 142 publications

(255 reference statements)

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“…HSP90 transcription is activated by Hsf1, which is negatively regulated by interaction with Hsp90 as an autoregulatory loop (Leach et al 2012). Interestingly, HSP90 expression was rapidly induced in both WT and sch9D strains by temperature upshift, which is in stark contrast to HSF1 expression patterns ( Figure 4E and Figure S5).…”

Section: Resultscontrasting

confidence: 39%

“…and also serves as a key negative feedback regulator of Hsf1 in most fungi (Leach et al 2012). In our study, we also found that HSP90 expression was strongly induced upon temperature upshift.…”

supporting

confidence: 64%

“…In Candida albicans, Hsp90 interacts with Hsf1 and negatively regulates Hsf1 activity (Leach et al 2012). Therefore, it is possible that increased expression of Hsp90 may inhibit Hsf1, which subsequently reduces autoinduction of HSF1.…”

mentioning

confidence: 99%

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Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans

et al. 2017

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Thermotolerance is a crucial virulence attribute for human pathogens, including the fungus Cryptococcus neoformans that causes fatal meningitis in humans. Loss of the protein kinase Sch9 increases C. neoformans thermotolerance, but its regulatory mechanism has remained unknown. Here, we studied the Sch9-dependent and Sch9-independent signaling networks modulating C. neoformans thermotolerance by using genome-wide transcriptome analysis and reverse genetic approaches. During temperature upshift, genes encoding for molecular chaperones and heat shock proteins were upregulated, whereas those for translation, transcription, and sterol biosynthesis were highly suppressed. In this process, Sch9 regulated basal expression levels or induced/repressed expression levels of some temperature-responsive genes, including heat shock transcription factor (HSF1) and heat shock proteins (HSP104 and SSA1). Notably, we found that the HSF1 transcript abundance decreased but the Hsf1 protein became transiently phosphorylated during temperature upshift. Nevertheless, Hsf1 is essential for growth and its overexpression promoted C. neoformans thermotolerance. Transcriptome analysis using an HSF1 overexpressing strain revealed a dual role of Hsf1 in the oxidative stress response and thermotolerance. Chromatin immunoprecipitation demonstrated that Hsf1 binds to the step-type like heat shock element (HSE) of its target genes more efficiently than to the perfect-or gap-type HSE. This study provides insight into the thermotolerance of C. neoformans by elucidating the regulatory mechanisms of Sch9 and Hsf1 through the genome-scale identification of temperature-dependent genes. KEYWORDS Hsf1; Sch9; transcriptome analysis; high temperature; Cryptococcus neoformans R ESPONSE and adaptation to their host's physiological temperature, 37°, are key virulence attributes for most human fungal pathogens that infect from natural environments at ambient temperature. Cryptococcus neoformans is an example of such a pathogen. This basidiomycetous fungus exists in diverse environment niches and generates infectious yeast cells or spores through bisexual and unisexual differentiation, which are inhaled through the respiratory tract in the host and initially colonize the lungs (Idnurm et al. 2005;Lin and Heitman 2006). C. neoformans is subsequently disseminated into the bloodstream, breaches the central nervous system, and eventually elicits fatal meningoencephalitis, responsible for an estimated hundreds of thousands of deaths annually (Park et al. 2009). During this infectious process, the ability to sense and adapt to temperature upshift are crucial factors for the pathogen to establish the initial colonization of the lungs. Therefore, most mutants that are severely defective in thermotolerance tend to be highly attenuated in virulence. Due to such reasons, signaling cascades governing thermotolerance in fungi have been intensively investigated toward their exploitation as potential antifungal drug targets (Bahn et al. 2007;Bahn and Jung 2013). In...

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Section: Resultscontrasting

confidence: 39%

supporting

confidence: 64%

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Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans

et al. 2017

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“…How Hsp90 deals with different kinds of environmental stresses is well documented (23,28). Yet, few studies have examined its role in carbon source metabolism.…”

mentioning

confidence: 99%

“…By associating with different cochaperones and cofactors, Hsp90 helps a wide range of client proteins involved in various biological processes (19,(23)(24)(25). For instance, with the cooperation of the Hsp70 and Hsp40 cochaperones, Hsp90 binds to the glucocorticoid receptor to maintain it in a conformation required for steroid hormone binding (26).…”

mentioning

confidence: 99%

Hsp90 Maintains Proteostasis of the Galactose Utilization Pathway To Prevent Cell Lethality

Gopinath

Leu

2016

Molecular and Cellular Biology

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bHsp90 is a molecular chaperone that aids in the folding of its metastable client proteins. Past studies have shown that it can exert a strong impact on some cellular pathways by controlling key regulators. However, it is unknown whether several components of a single pathway are collectively regulated by Hsp90. Here, we observe that Hsp90 influences the protein abundance of multiple Gal proteins and the efficiency of galactose utilization even after the galactose utilization pathway (GAL pathway) is fully induced. The effect of Hsp90 on Gal proteins is not at the transcriptional level. Moreover, Gal1 is found to physically interact with Hsp90, and its stability is reduced in low-Hsp90 cells. When Hsp90 is compromised, several Gal proteins form protein aggregates that colocalize with the disaggregase Hsp104. These results suggest that Gal1 and other Gal proteins are probably the clients of Hsp90. An unbalanced GAL pathway has been known to cause fatal growth arrest due to accumulation of toxic galactose metabolic intermediates. It is likely that Hsp90 chaperones multiple Gal proteins to maintain proteostasis and prevent cell lethality especially in a fluctuating environment.

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Design, synthesis, and evaluation of novel 3,4‐isoxazolediamide derivatives for the combination treatment of azole‐resistant candidiasis

Liu

Sun

Gao

et al. 2022

Archiv der Pharmazie

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Invasive fungal infections are emerging as serious infectious diseases worldwide.Due to the frequent emergence of resistance, the cure for invasive fungal infections is often unachievable. The molecular chaperone Hsp90 provides a promising target because it supports survival, virulence, and drug resistance in a variety of pathogens.Herein, we report on the structural optimization and structure-activity relationship studies of 3,4-isoxazolediamide analogs. As a new class of fungal Hsp90 inhibitor, compound B25 was found to have good synergistic effects with fluconazole and to avoid potential mammalian toxicity. It also showed remarkable metabolic stability in vitro. Collectively, B25 could be a promising lead compound for drug discovery targeting fungal Hsp90 and deserves further investigation.

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Fungal Hsp90: a biological transistor that tunes cellular outputs to thermal inputs

Cited by 87 publications

References 142 publications

Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans

Rewiring of Signaling Networks Modulating Thermotolerance in the Human Pathogen Cryptococcus neoformans

Hsp90 Maintains Proteostasis of the Galactose Utilization Pathway To Prevent Cell Lethality

Design, synthesis, and evaluation of novel 3,4‐isoxazolediamide derivatives for the combination treatment of azole‐resistant candidiasis

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