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Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2

ABSTRACT: The cell wall is essential for viability of fungi and is an effective drug target in pathogens such as Candida albicans. The contribution of posttranscriptional gene regulators to cell wall integrity in C. albicans is unknown. We show that the C. albicans Ccr4-Pop2 mRNA deadenylase, a regulator of mRNA stability and translation, is required for cell wall integrity. The ccr4/pop2 mutants display reduced wall β-glucans and sensitivity to the echinocandin caspofungin. Moreover, the deadenylase mutants are compromised for filamentation and virulence. We demonstrate that defective cell walls in the ccr4/pop2 mutants are linked to dysfunctional mitochondria and phospholipid imbalance. To further understand mitochondrial function in cell wall integrity, we screened a Saccharomyces cerevisiae collection of mitochondrial mutants. We identify several mitochondrial proteins required for caspofungin tolerance and find a connection between mitochondrial phospholipid homeostasis and caspofungin sensitivity. We focus on the mitochondrial outer membrane SAM complex subunit Sam37, demonstrating it is required for both trafficking of phospholipids between the ER and mitochondria and cell wall integrity. Moreover, in C. albicans also Sam37 is essential for caspofungin tolerance. Our study provides the basis for an integrative view of mitochondrial function in fungal cell wall biogenesis and resistance to echinocandin antifungal drugs.

ORGANISM(S): Candida albicans

PROVIDER: GSE25891 | GEO | 2010/12/10

SECONDARY ACCESSION(S): PRJNA135877

REPOSITORIES: GEO

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Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2

Project description:The cell wall is essential for viability of fungi and is an effective drug target in pathogens such as Candida albicans. The contribution of posttranscriptional gene regulators to cell wall integrity in C. albicans is unknown. We show that the C. albicans Ccr4-Pop2 mRNA deadenylase, a regulator of mRNA stability and translation, is required for cell wall integrity. The ccr4/pop2 mutants display reduced wall β-glucans and sensitivity to the echinocandin caspofungin. Moreover, the deadenylase mutants are compromised for filamentation and virulence. We demonstrate that defective cell walls in the ccr4/pop2 mutants are linked to dysfunctional mitochondria and phospholipid imbalance. To further understand mitochondrial function in cell wall integrity, we screened a Saccharomyces cerevisiae collection of mitochondrial mutants. We identify several mitochondrial proteins required for caspofungin tolerance and find a connection between mitochondrial phospholipid homeostasis and caspofungin sensitivity. We focus on the mitochondrial outer membrane SAM complex subunit Sam37, demonstrating it is required for both trafficking of phospholipids between the ER and mitochondria and cell wall integrity. Moreover, in C. albicans also Sam37 is essential for caspofungin tolerance. Our study provides the basis for an integrative view of mitochondrial function in fungal cell wall biogenesis and resistance to echinocandin antifungal drugs. Two-color experimental design comparing cells with a double-knockout of the CCR4 genes to cells with a reintegrated CCR4 gene.

2010-12-10 | E-GEOD-25891 | biostudies-arrayexpress

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Project description:The cyclic AMP-protein kinase A pathway has a central role in the biology of Candida albicans, a prominent fungal pathogen of humans. The two catalytic subunits for cyclic AMP-dependent protein kinase, Tpk1 (orf19.4892) and Tpk2 (orf19.2277), have divergent roles, and most studies indicate a more pronounced role for Tpk2. Here we dissect two Tpk1-responsive properties: adherence and cell wall integrity. Homozygous tpk1/tpk1 mutants are hyperadherent, and a Tpk1 defect enables biofilm formation in the absence of Bcr1, a central transcriptional regulator of biofilm adhesins. Microarray analysis revealed an enrichment for cell wall and surface functions among Tpk1-repressed genes, and overexpression of individual target genes indicates that cell surface proteins Als1, Als2, Als4, Csh1, and Csp37 contribute to Tpk1-regulated adherence. Tpk1 is also required for cell wall integrity, but has no role in the cell wall integrity gene expression response. Interestingly, increased expression of the adhesin gene ALS2 conferred a cell wall defect, as manifested in hypersensitivity to the cell wall inhibitor caspofungin and a shallow cell wall structure. Our findings indicate that Tpk1 has a central role in C. albicans cell wall properties that is exerted through repression of select cell surface protein genes. Two-color microarrays using a closed-loop experimental design to determine the effects of a M-bM-^HM-^Ftpk1 deletion in the absence or presence of the antifungal Caspofungin (CF)

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Project description:Caspofungin resistance is a great concern, as the echinocandin drugs are recommended as first-line therapy for invasive candidiasis. Echinocandin resistance is conferred by mutations in FKS genes. Nevertheless, some pathways which regulate cellular stress responses could be crucial for enabling the evolution and maintenance of drug resistance. In this work, the first objective was to identify resistant mechanisms by whole genome sequencing in echinocandin-resistant C. glabrata. Then, studies of the proteomic response to caspofungin exposure and the analysis of the impact of calcineurin inhibitors on susceptibility, stress tolerance, biofilm formation, and pathogenicity in Galleria mellonella were conducted. The caspofungin resistant isolate only presented mutation in the FKS gene. Based on proteomic results, we identified 21 proteins whose abundance changed in response to caspofungin exposure. Some of these proteins are involved in wall biosynthesis, pathogenesis, and response to stress. Also, we showed that antifungal drugs in combination with CaM/Cal inhibitors could be an excellent therapeutic option, proved in an in-vitro and in-vivo model. Results, that could be potentially used to improve the outcomes of fungal diseases, especially now that antifungal resistance is increasing.

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Expression data from wt, pop2, pbp1, and mpt5-deletion yeast cells.

Project description:The S. cerevisiae Pop2 protein is an exonuclease in the Ccr4-Not complex that is a conserved regulator of gene expression. Pop2 regulates gene expression post-transcriptionally by shortening the poly(A) tail of mRNA. A previous study has shown that Pop2 is phosphorylated at threonine 97 (T97) by Yak1 protein kinase in response to glucose limitation. However, the physiological importance of Pop2 phosphorylation remains unknown. In this study, we found that Pop2 is phosphorylated at serine 39 (S39) under unstressed conditions. The dephosphorylation of S39 was occurred within 1 min after glucose depletion, and the addition of glucose to the glucose-deprived culture recovered this phosphorylation, suggesting that Pop2 phosphorylation at S39 is regulated by glucose. We previously reported that Pop2 takes a part in the cell wall integrity pathway by regulation of LRG1 mRNA; however, S39 phosphorylation of Pop2 is not involved in LRG1 expression. On the other hand, Pop2 phosphorylation at S39 is involved in the expression of HSP12 and HSP26, encoding small heat shock proteins. In medium supplemented with glucose, Pop2 might be phosphorylated at S39 by Pho85 kinase to repress the expression of HSP12 and HSP26. Glucose starvation inactivated Pho85, which resulted in the derepression of HSP12 and HSP26. Thus, Pop2 phosphorylation at S39 is important for Pop2 to repress the expression of stress response genes, HSP12 and HSP26, in the presence of glucose. Our results suggest that Pop2 phosphorylation by Pho85 kinase is a part of the glucose sensing system in yeast.

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Project description:Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2

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