Yeast casein kinase 2 governs morphology, biofilm formation, cell wall integrity, and host cell damage of Candida albicans

Jung, Sook-In; Rodríguez, Natalie; Irrizary, Jihyun; Liboro, Karl; Bogarin, Thania; Macias, Marlene; Eivers, Edward; Porter, Edith; Filler, Scott G.; Park, Hyun‐Sook

doi:10.1371/journal.pone.0187721

Cited by 19 publications

(21 citation statements)

References 85 publications

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“…This gene remains, however, a good candidate for future investigations on molecular mechanisms behind FLC tolerance. Interestingly, YCK2 was showed recently as interfering with caspofungin resistance (Caplan et al, 2020) and was shown earlier to be involved in response to FLC (Jung et al, 2017). The single strain assay also confirmed our pool enrichment protocol to be a valuable approach for the identification of putative positive mediators of FLC tolerance.…”

Section: Discussionsupporting

confidence: 69%

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Delarze¹,

Brandt²,

Trachsel³

et al. 2020

Front. Microbiol.

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Candida albicans is an important human pathogen and a major concern in intensive care units around the world. C. albicans infections are associated with a high mortality despite the use of antifungal treatments. One of the causes of therapeutic failures is the acquisition of antifungal resistance by mutations in the C. albicans genome. Fluconazole (FLC) is one of the most widely used antifungal and mechanisms of FLC resistance occurring by mutations have been extensively investigated. However, some clinical isolates are known to be able to survive at high FLC concentrations without acquiring resistance mutations, a phenotype known as tolerance. Mechanisms behind FLC tolerance are not well studied, mainly due to the lack of a proper way to identify and quantify tolerance in clinical isolates. We proposed here culture conditions to investigate FLC tolerance as well as an easy and efficient method to identity and quantify tolerance to FLC. The screening of C. albicans strain collections revealed that FLC tolerance is pH- and strain-dependent, suggesting the involvement of multiple mechanisms. Here, we addressed the identification of FLC tolerance mediators in C. albicans by an overexpression strategy focusing on 572 C. albicans genes. This strategy led to the identification of two transcription factors, CRZ1 and GZF3 . CRZ1 is a C2H2-type transcription factor that is part of the calcineurin-dependent pathway in C. albicans , while GZF3 is a GATA-type transcription factor of unknown function in C. albicans . Overexpression of each gene resulted in an increase of FLC tolerance, however, only the deletion of CRZ1 in clinical FLC-tolerant strains consistently decreased their FLC tolerance. Transcription profiling of clinical isolates with variable levels of FLC tolerance confirmed a calcineurin-dependent signature in these isolates when exposed to FLC.

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Section: Discussionsupporting

confidence: 69%

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Delarze¹,

Brandt²,

Trachsel³

et al. 2020

Front. Microbiol.

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“…Our recent study found that a loss of C. albicans Yeast Casein Kinase 2 (CaYck2) function results in constitutive pseudohyphae formation and upregulation of hyphal-specific genes (HSGs), suggesting that CaYck2 serves as a negative regulator of hyphae formation. YCK2 deletion mutant strain ( yck2 Δ strain) has significantly increased expression of UME6, a transcription factor involved in hyphal transition, and its downstream HSGs such as ALS3 and HWP1 ( Jung et al., 2017 ). The yck2 Δ strain also shows hypersensitivity to cell wall damaging agents and compensatory chitin deposit on the cell wall ( Jung et al., 2017 ).…”

Section: Introductionmentioning

confidence: 99%

“…YCK2 deletion mutant strain ( yck2 Δ strain) has significantly increased expression of UME6, a transcription factor involved in hyphal transition, and its downstream HSGs such as ALS3 and HWP1 ( Jung et al., 2017 ). The yck2 Δ strain also shows hypersensitivity to cell wall damaging agents and compensatory chitin deposit on the cell wall ( Jung et al., 2017 ). These results suggest that CaYck2p plays an important role in maintaining cell wall integrity and the morphogenic switch from yeast to hyphae.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic and Metabolomic Analysis Revealed Roles of Yck2 in Carbon Metabolism and Morphogenesis of Candida albicans

Liboro

Lim

et al. 2021

Front. Cell. Infect. Microbiol.

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Candida albicans is a part of the normal microbiome of human mucosa and is able to thrive in a wide range of host environments. As an opportunistic pathogen, the virulence of C. albicans is tied to its ability to switch between yeast and hyphal morphologies in response to various environmental cues, one of which includes nutrient availability. Thus, metabolic flexibility plays an important role in the virulence of the pathogen. Our previous study has shown that C. albicans Yeast Casein Kinase 2 (CaYck2) regulates the yeast-to-hyphal switch, but its regulatory mechanisms remain unknown. This study further elucidated the role of Yck2 in governing morphology and carbon metabolism by analyzing the transcriptome and metabolome of the C. albicans YCK2 deletion mutant strain (yck2Δ strain) in comparison to the wild type strain. Our study revealed that loss of CaYck2 perturbs carbon metabolism, leading to a transcriptional response that resembles a transcriptional response to glucose starvation with coinciding intracellular accumulation of glucose and depletion of TCA cycle metabolites. This shift in the metabolome is likely mediated by derepression of glucose-repressed genes in the Mig1/2-mediated glucose sensing pathway and by downregulation of glycolytic genes, possibly through the Rgt1-mediated SRR pathway. In addition, genes involved in beta-oxidation, glyoxylate cycle, oxidative stress response, and arginine biosynthesis were upregulated in the yck2Δ strain, which is highly reminiscent of C. albicans engulfment by macrophages. This coincides with an increase in arginine degradation intermediates in the yck2Δ strain, suggesting arginine catabolism as a potential mechanism of CaYck2-mediated filamentation as seen during C. albicans escape from macrophages. Transcriptome analysis also shows differential expression of hyphal transcriptional regulators Nrg1 and Ume6. This suggests dysregulation of hyphal initiation and elongation in the yck2Δ strain which may lead to the constitutive pseudohyphal phenotype of this strain. Metabolome analysis also detected a high abundance of methyl citrate cycle intermediates in the yck2Δ strain, suggesting the importance of CaYck2 in this pathway. Taken together, we discovered that CaYck2 is an integral piece of carbon metabolism and morphogenesis of C. albicans.

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“…In most eukaryotes, the CK2 protein kinase is a tetramer consisting of two catalytic alpha subunits (α and α′) and a dimer of regulatory beta (β) subunits 14 . CK2 has been described as a pleiotropic and constitutively active kinase shown to be associated with the phosphorylation of hundreds of substrates in different eukaryotes including yeast and humans [15][16][17][18] . CK2 substrates are found in various cellular compartments such as the nucleus, the Golgi apparatus, the endoplasmic reticulum, and the cytoplasm 14,19 .…”

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confidence: 99%

The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis

et al. 2021

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Casein kinase 2 (CK2) is a pleiotropic kinase phosphorylating substrates in different cellular compartments in eukaryotes. In the malaria parasite Plasmodium falciparum, PfCK2 is vital for asexual proliferation of blood-stage parasites. Here, we applied CRISPR/Cas9-based gene editing to investigate the function of the PfCK2α catalytic subunit in gametocytes, the sexual forms of the parasite that are essential for malaria transmission. We show that PfCK2α localizes to the nucleus and cytoplasm in asexual and sexual parasites alike. Conditional knockdown of PfCK2α expression prevented the transition of stage IV into transmission-competent stage V gametocytes, whereas the conditional knockout of pfck2a completely blocked gametocyte maturation already at an earlier stage of sexual differentiation. In summary, our results demonstrate that PfCK2α is not only essential for asexual but also sexual development of P. falciparum blood-stage parasites and encourage studies exploring PfCK2α as a potential target for dual-active antimalarial drugs.

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Yeast casein kinase 2 governs morphology, biofilm formation, cell wall integrity, and host cell damage of Candida albicans

Cited by 19 publications

References 85 publications

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Identification and Characterization of Mediators of Fluconazole Tolerance in Candida albicans

Transcriptomic and Metabolomic Analysis Revealed Roles of Yck2 in Carbon Metabolism and Morphogenesis of Candida albicans

The catalytic subunit of Plasmodium falciparum casein kinase 2 is essential for gametocytogenesis

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