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PMID: 22687514 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Rapid redistribution of phosphatidylinositol-(4,5)-bisphosphate and septins during the Candida albicans response to caspofungin.

Antimicrobial agents and chemotherapy ·Vol. 56 ·No. 9 ·2012-09-00 ·Pages 4614-24

Badrane H, Nguyen MH, Blankenship JR, Cheng S, Hao B, Mitchell AP, Clancy CJ

Abstract

We previously showed that phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] and septin regulation play major roles in maintaining Candida albicans cell wall integrity in response to caspofungin and other stressors. Here, we establish a link between PI(4,5)P2 signaling and septin localization and demonstrate that rapid redistribution of PI(4,5)P2 and septins is part of the natural response of C. albicans to caspofungin. First, we studied caspofungin-hypersusceptible C. albicans irs4 and inp51 mutants, which have elevated PI(4,5)P2 levels due to loss of PI(4,5)P2-specific 5'-phosphatase activity. PI(4,5)P2 accumulated in discrete patches, rather than uniformly, along surfaces of mutants in yeast and filamentous morphologies, as visualized with a green fluorescent protein (GFP)-pleckstrin homology domain. The patches also contained chitin (calcofluor white staining) and cell wall protein Rbt5 (Rbt5-GFP). By transmission electron microscopy, patches corresponded to plasma membrane invaginations that incorporated cell wall material. Fluorescently tagged septins Cdc10 and Sep7 colocalized to these sites, consistent with well-described PI(4,5)P2-septin physical interactions. Based on expression patterns of cell wall damage response genes, irs4 and inp51 mutants were firmly positioned within a group of caspofungin-hypersusceptible, septin-regulatory protein kinase mutants. irs4 and inp51 were linked most closely to the gin4 mutant by expression profiling, PI(4,5)P2-septin-chitin redistribution and other phenotypes. Finally, sublethal 5-min exposure of wild-type C. albicans to caspofungin resulted in redistribution of PI(4,5)P2 and septins in a manner similar to those of irs4, inp51, and gin4 mutants. Taken together, our data suggest that the C. albicans Irs4-Inp51 5'-phosphatase complex and Gin4 function upstream of PI(4,5)P2 and septins in a pathway that helps govern responses to caspofungin.

MeSH Terms
Antifungal Agents/pharmacology Biological Transport/drug effects Candida albicans/drug effects,genetics,metabolism Caspofungin Cell Wall/drug effects,genetics,metabolism Chitin/metabolism Cyclin-Dependent Kinases/genetics,metabolism Echinocandins/pharmacology Fungal Proteins/genetics,metabolism Gene Expression Regulation, Fungal Genes, Reporter Green Fluorescent Proteins Insulin Receptor Substrate Proteins/genetics,metabolism Lipopeptides Phosphatidylinositol Phosphates/metabolism Phosphoric Monoester Hydrolases/genetics,metabolism Septins/genetics,metabolism Signal Transduction Stress, Physiological
Chemicals
Antifungal Agents Echinocandins Fungal Proteins Insulin Receptor Substrate Proteins Lipopeptides Phosphatidylinositol Phosphates Chitin Green Fluorescent Proteins Cyclin-Dependent Kinases Phosphoric Monoester Hydrolases Septins Caspofungin
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Badrane Hassan
Division of Infectious Diseases, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Nguyen M Hong
Blankenship Jill R
Cheng Shaoji
Hao Binghua
Mitchell Aaron P
Clancy Cornelius J
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Article Info
Journal
Antimicrobial agents and chemotherapy
Abbr.
Antimicrob Agents Chemother
ISSN
1098-6596
DOI
10.1128/AAC.00112-12
Published
2012-09-00
Epub
2012-00-11
Pages
4614-24
Language
English
Region
United States
NLM ID
0315061
PMCID
PMC3421880
Subset
IM
Grants
NIDCR NIH HHS · R56 DE020831 · United States
NIDCR NIH HHS · R56DE020831 · United States
External Links
PubMed source DOI: 10.1128/AAC.00112-12 PMC Full Text View journal details
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