The mannoprotein TIR3 (CAGL0C03872g) is required for sterol uptake in Candida glabrata

Inukai, Tatsuya; Nagi, Minoru; Morita, Akihiro; Tanabe, Koichi; Aoyama, Toshihiro; Miyazaki, Yoshitsugu; Bard, Martin; Nakayama, Hironobu

doi:10.1016/j.bbalip.2014.11.002

Cited by 10 publications

(15 citation statements)

References 43 publications

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“…As mentioned above, Dan1 mediates sterol uptake [27,31]. Complementation experiments in Candida glabrata using budding yeast TIR3 suggest that TIR3 might also have a role in sterol import [42]. There is no evidence that other PAU / DAN / TIR genes are also involved in sterol uptake.…”

Section: Functions Of Ecm22 Upc2 Sut1 and Sut2 In Budding Yeastmentioning

confidence: 99%

“…Upc2A upregulates the expression of several genes in this process including UPC2B and AUS1 , the sole ortholog of budding AUS1 and PDR11 [74,98,99]. Expression of TIR3 , the ortholog of budding yeast TIR3 , is also induced by Upc2A [42]. The plasma membrane protein Aus1 and the cell wall protein Tir3 cooperate in sterol uptake [42,99].…”

Section: Orthologs Of Ecm22 Upc2 Sut1 and Sut2 In Other Speciesmentioning

confidence: 99%

“…Expression of TIR3 , the ortholog of budding yeast TIR3 , is also induced by Upc2A [42]. The plasma membrane protein Aus1 and the cell wall protein Tir3 cooperate in sterol uptake [42,99]. …”

Section: Orthologs Of Ecm22 Upc2 Sut1 and Sut2 In Other Speciesmentioning

confidence: 99%

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From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2

Joshua

Höfken

2017

IJMS

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Zinc cluster proteins are a large family of transcriptional regulators with a wide range of biological functions. The zinc cluster proteins Ecm22, Upc2, Sut1 and Sut2 have initially been identified as regulators of sterol import in the budding yeast Saccharomyces cerevisiae. These proteins also control adaptations to anaerobic growth, sterol biosynthesis as well as filamentation and mating. Orthologs of these zinc cluster proteins have been identified in several species of Candida. Upc2 plays a critical role in antifungal resistance in these important human fungal pathogens. Upc2 is therefore an interesting potential target for novel antifungals. In this review we discuss the functions, mode of actions and regulation of Ecm22, Upc2, Sut1 and Sut2 in budding yeast and Candida.

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Section: Functions Of Ecm22 Upc2 Sut1 and Sut2 In Budding Yeastmentioning

confidence: 99%

Section: Orthologs Of Ecm22 Upc2 Sut1 and Sut2 In Other Speciesmentioning

confidence: 99%

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From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2

Joshua

Höfken

2017

IJMS

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“…The C-terminal antibody binding region of the MP58 protein is the antigenic epitopes of C. albicans, and monoclonal antibodies targeting this epitope can play a protective role in the serum treatment experiments in a mouse model of candidiasis [23]. In Candida glabrata, the mannoprotein Tir3 is necessary for sterol uptake [24]. In Talaromyces (Penicillium) marneffei, the mannoprotein Mp1p was proved to be an essential virulence factor, mediating virulence by enhancing T. marneffei's survival inside macrophages [25,26].…”

Section: Introductionmentioning

confidence: 99%

A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

Han

Liu

2020

Pathogens

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The capsule of the fungal pathogen Cryptococcus neoformans consists of glucuronoxylomannan (GXM), glucuronoxylomannogalactan (GXMGal), and mannoproteins (MPs). MPs are a kind of glycoproteins with low content but high immunogenicity, which can stimulate the immune protection of the host. However, there is not much information about the role of mannoproteins in virulence of the human fungal pathogen C. neoformans. In this study, we reported the identification and functional analysis of a predicted mannoprotein Cmp1 that regulates fungal virulence in C. neoformans. Gene expression pattern analysis indicates that the CMP1 gene was ubiquitously expressed at all stages of cryptococcal development. Subcellular localization analysis indicated that Cmp1 was localized in the cytoplasm of cryptococcal cells. Disruption or overexpression of CMP1 results in impairing capsule formation in Cryptococcus, but it does not affect the melanin production and sensitivity under various stress conditions, nor does it affect the sexual reproduction process of Cryptococcus. Survival assay showed that the pathogenicity of the cmp1Δ mutant or the CMP1 overexpression strain was significantly attenuated in a murine inhalation model of cryptococcosis. In conclusion, our findings implied that the mannoprotein Cmp1 is required for the virulence of C. neoformans.

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“…Sterol uptake appears to confer resistance to antifungal drugs since mutant strains of Candida species lacking AUS1 and TIR3 , the sterol influx transporters ( 3 ), or UPC2 , the transcription factor that controls AUS1 and TIR3 expression ( 3 – 5 ), exhibit reduced uptake of cholesterol and are hypersensitive to azoles ( 6 , 7 ), whereas enhanced UPC2 or AUS1 expression and cholesterol uptake have been implicated in the azole-resistant phenotype ( 6 , 7 ). Furthermore, several studies have even suggested that pathogenic fungi can scavenge free sterols for the cell membrane, including cholesterol, resulting in resistance to polyene and azole antifungals ( 8 ).…”

Section: Introductionmentioning

confidence: 99%

Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candidaï¿½glabrata under azole and hypoxic stress

Tsai

Mandal

et al. 2018

Mol Med Report

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Pathogenic fungi, including Candida glabrata, develop strategies to grow and survive both in vitro and in vivo under azole stress. However, the mechanisms by which yeast cells counteract the inhibitory effects of azoles are not completely understood. In the current study, it was demonstrated that the expression of the ergosterol biosynthetic genes ERG2, ERG3, ERG4, ERG10, and ERG11 was significantly upregulated in C. glabrata following fluconazole treatment. Inhibiting ergosterol biosynthesis using fluconazole also increased the expression of the sterol influx transporter AUS1 and the sterol metabolism regulators SUT1 and UPC2 in fungal cells. The microarray study quantified 35 genes with elevated mRNA levels, including AUS1, TIR3, UPC2, and 8 ERG genes, in a C. glabrata mutant strain lacking ERG1, indicating that sterol importing activity is increased to compensate for defective sterol biosynthesis in cells. Bioinformatic analyses further revealed that those differentially expressed genes were involved in multiple cellular processes and biological functions, such as sterol biosynthesis, lipid localization, and sterol transport. Finally, to assess whether sterol uptake affects yeast susceptibility to azoles, we generated a C. glabrata aus1∆ mutant strain. It was shown that loss of Aus1p in C. glabrata sensitized the pathogen to azoles and enhanced the efficacy of drug exposure under low oxygen tension. In contrast, the presence of exogenous cholesterol or ergosterol in medium rendered the C. glabrata AUS1 wild-type strain highly resistant to fluconazole and voriconazole, suggesting that the sterol importing mechanism is augmented when ergosterol biosynthesis is suppressed in the cell, thus allowing C. glabrata to survive under azole pressure. On the basis of these results, it was concluded that sterol uptake and sterol biosynthesis may act coordinately and collaboratively to sustain growth and to mediate antifungal resistance in C. glabrata through dynamic gene expression in response to azole stress and environmental challenges.

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The mannoprotein TIR3 (CAGL0C03872g) is required for sterol uptake in Candida glabrata

Cited by 10 publications

References 43 publications

From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2

From Lipid Homeostasis to Differentiation: Old and New Functions of the Zinc Cluster Proteins Ecm22, Upc2, Sut1 and Sut2

A Predicted Mannoprotein Cmp1 Regulates Fungal Virulence in Cryptococcus neoformans

Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candidaï¿½glabrata under azole and hypoxic stress

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