1. Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2.
- Author
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Dagley MJ, Gentle IE, Beilharz TH, Pettolino FA, Djordjevic JT, Lo TL, Uwamahoro N, Rupasinghe T, Tull DL, McConville M, Beaurepaire C, Nantel A, Lithgow T, Mitchell AP, and Traven A
- Subjects
- Animals, Candida albicans drug effects, Candida albicans metabolism, Candida albicans pathogenicity, Caspofungin, Cell Wall chemistry, Cell Wall drug effects, Echinocandins pharmacology, Fungal Proteins genetics, Gene Expression Profiling, Gene Expression Regulation, Fungal, Homeostasis, Lipopeptides, Mice, Mice, Inbred BALB C, Mitochondria ultrastructure, Mutation, Oligonucleotide Array Sequence Analysis, Phospholipids analysis, Polyadenylation, RNA, Fungal genetics, Ribonucleases genetics, Saccharomyces cerevisiae drug effects, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Virulence, beta-Glucans analysis, Candida albicans genetics, Cell Wall ultrastructure, Fungal Proteins metabolism, Mitochondria metabolism, Ribonucleases metabolism
- 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 post-transcriptional 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 that 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., (© 2010 Blackwell Publishing Ltd.)
- Published
- 2011
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