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

• Published in: Molecular microbiology 2011-02, Vol.79 (4), p.968-989
• Main Authors: Dagley, Michael J, Gentle, Ian E, Beilharz, Traude H, Pettolino, Filomena A, Djordjevic, Julianne T, Lo, Tricia L, Uwamahoro, Nathalie, Rupasinghe, Thusitha, Tull, Dedreja L, McConville, Malcolm, Beaurepaire, Cecile, Nantel, André, Lithgow, Trevor, Mitchell, Aaron P, Traven, Ana
• Format: Article
• Language: English
• Subjects: Animals; beta-Glucans - analysis; Biological and medical sciences; Candida albicans; Candida albicans - drug effects; Candida albicans - genetics; Candida albicans - metabolism; Candida albicans - pathogenicity; Cell Wall - chemistry; Cell Wall - drug effects; Cell Wall - ultrastructure; Cells; Echinocandins - pharmacology; Fundamental and applied biological sciences. Psychology; Fungal Proteins - genetics; Fungal Proteins - metabolism; Fungi; Gene Expression Profiling; Gene Expression Regulation, Fungal; Homeostasis; Lipids; Lipopeptides; Mice; Mice, Inbred BALB C; Microbiology; Miscellaneous; Mitochondria - metabolism; Mitochondria - ultrastructure; Mutation; Mycology; Oligonucleotide Array Sequence Analysis; Phospholipids - analysis; Polyadenylation; Proteins; Ribonucleases - genetics; Ribonucleases - metabolism; Ribonucleic acid; RNA; RNA, Fungal - genetics; Saccharomyces cerevisiae; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Virulence; Yeast
• ISSN: 0950-382X; 1365-2958
• DOI: 10.1111/j.1365-2958.2010.07503.x

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.