Calcineurin is required for virulence of Cryptococcus neoformans

The EMBO Journal
A OdomJ Heitman

Abstract

Cyclosporin A (CsA) and FK506 are antimicrobial, immunosuppressive natural products that inhibit signal transduction. In T cells and Saccharomyces cerevisiae, CsA and FK506 bind to the immunophilins cyclophilin A and FKBP12 and the resulting complexes inhibit the Ca2+-regulated protein phosphatase calcineurin. We find that growth of the opportunistic fungal pathogen Cryptococcus neoformans is sensitive to CsA and FK506 at 37 degrees C but not at 24 degrees C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature. Genetic evidence supports a model in which immunophilin-drug complexes inhibit calcineurin to prevent growth at 37 degrees C. The gene encoding the C. neoformans calcineurin A catalytic subunit was cloned and disrupted by homologous recombination. Calcineurin mutant strains are viable but do not survive in vitro conditions that mimic the host environment (elevated temperature, 5% CO2 or alkaline pH) and are no longer pathogenic in an animal model of cryptococcal meningitis. Introduction of the wild-type calcineurin A gene complemented these growth defects and restored virulence. Our findings demonstrate that calcineurin is required for C. neoformans virulence and may ...Continue Reading

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Citations

Sep 27, 2002·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Deborah S Fox, Joseph Heitman
Apr 1, 1999·Cell Biochemistry and Biophysics·C S Hemenway, J Heitman
Feb 18, 2009·Molecular Genetics and Genomics : MGG·Pamela Hui Peng GanAdrienne R Hardham
Nov 19, 2003·Biochemical and Biophysical Research Communications·Zoe Hilioti, Kyle W Cunningham
Nov 19, 2003·Biochemical and Biophysical Research Communications·Peter R Kraus, Joseph Heitman
Dec 7, 2002·Molecular and Biochemical Parasitology·Alessandro RossiMo-Quen Klinkert
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Jan 27, 2010·Antimicrobial Agents and Chemotherapy·Taiga MiyazakiShigeru Kohno

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