Document Detail

Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2.
MedLine Citation:
PMID:  21299651     Owner:  NLM     Status:  MEDLINE    
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.
Michael J Dagley; Ian E Gentle; Traude H Beilharz; Filomena A Pettolino; Julianne T Djordjevic; Tricia L Lo; Nathalie Uwamahoro; Thusitha Rupasinghe; Dedreja L Tull; Malcolm McConville; Cecile Beaurepaire; André Nantel; Trevor Lithgow; Aaron P Mitchell; Ana Traven
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-12-30
Journal Detail:
Title:  Molecular microbiology     Volume:  79     ISSN:  1365-2958     ISO Abbreviation:  Mol. Microbiol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-08     Completed Date:  2011-06-09     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  8712028     Medline TA:  Mol Microbiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  968-89     Citation Subset:  IM    
Copyright Information:
© 2010 Blackwell Publishing Ltd.
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MeSH Terms
Candida albicans / drug effects,  genetics*,  metabolism,  pathogenicity
Cell Wall / chemistry,  drug effects,  ultrastructure*
Echinocandins / pharmacology
Fungal Proteins / genetics,  metabolism*
Gene Expression Profiling
Gene Expression Regulation, Fungal
Mice, Inbred BALB C
Mitochondria / metabolism*,  ultrastructure
Oligonucleotide Array Sequence Analysis
Phospholipids / analysis
RNA, Fungal / genetics
Ribonucleases / genetics,  metabolism*
Saccharomyces cerevisiae / drug effects,  genetics,  metabolism
beta-Glucans / analysis
Reg. No./Substance:
0/Echinocandins; 0/Fungal Proteins; 0/Phospholipids; 0/RNA, Fungal; 0/beta-Glucans; EC 3.1.-/Ribonucleases; EC 3.1.-/mRNA deadenylase; F0XDI6ZL63/caspofungin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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