title: 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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Melbourne, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dagley
authors.forename: Ian E
authors.initials: IE
authors.lastname: Gentle
authors.forename: Traude H
authors.initials: TH
authors.lastname: Beilharz
authors.forename: Filomena A
authors.initials: FA
authors.lastname: Pettolino
authors.forename: Julianne T
authors.initials: JT
authors.lastname: Djordjevic
authors.forename: Tricia L
authors.initials: TL
authors.lastname: Lo
authors.forename: Nathalie
authors.initials: N
authors.lastname: Uwamahoro
authors.forename: Thusitha
authors.initials: T
authors.lastname: Rupasinghe
authors.forename: Dedreja L
authors.initials: DL
authors.lastname: Tull
authors.forename: Malcolm
authors.initials: M
authors.lastname: McConville
authors.forename: Cecile
authors.initials: C
authors.lastname: Beaurepaire
authors.forename: André
authors.initials: A
authors.lastname: Nantel
authors.forename: Trevor
authors.initials: T
authors.lastname: Lithgow
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Mitchell
authors.forename: Ana
authors.initials: A
authors.lastname: Traven
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism / Q000472:pathogenicity; D000077336:Caspofungin; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure*; D054714:Echinocandins / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D006706:Homeostasis; D055666:Lipopeptides; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010743:Phospholipids / Q000032:analysis; D026723:Polyadenylation; D012331:RNA, Fungal / Q000235:genetics; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014774:Virulence; D047071:beta-Glucans / Q000032:analysis
chemical_list: D054714:Echinocandins; D005656:Fungal Proteins; D055666:Lipopeptides; D010743:Phospholipids; D012331:RNA, Fungal; D047071:beta-Glucans; D012260:Ribonucleases; C445084:mRNA deadenylase; D000077336:Caspofungin