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Eukaryotic Cell, September 2005, p. 1526-1538, Vol. 4, No. 9
1535-9778/05/$08.00+0     doi:10.1128/EC.4.9.1526-1538.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Calcineurin-Binding Protein Cbp1 Directs the Specificity of Calcineurin-Dependent Hyphal Elongation during Mating in Cryptococcus neoformans

Deborah S. Fox1* and Joseph Heitman2*

Research Institute for Children and Department of Pediatrics, Louisiana State Health Science Center, Children's Hospital, New Orleans, Louisiana 70118,1 Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina 277102

Received 19 April 2005/ Accepted 20 June 2005

Mating and virulence of the human fungal pathogen Cryptococcus neoformans are controlled by calcineurin, a serine-threonine-specific calcium-activated phosphatase that is the target of the immunosuppressive drugs cyclosporine A and FK506. In previous studies, a calcineurin binding protein (Cbp1, Rcn1, Dscr1/Csp1-3/MCIP1-3) that is conserved from yeasts to humans has been identified, but whether this protein functions to regulate calcineurin activity or facilitate calcineurin function as a signaling effector has been unclear. Here we show that, like calcineurin, Cbp1 is required for mating in C. neoformans. By contrast, Cbp1 plays no role in promoting calcineurin-dependent growth at 37°C and is not essential for haploid fruiting. Site-directed mutagenesis studies provide evidence that tandem phosphorylation and dephosphorylation of two serine residues in the conserved SP repeat motif are critical for Cbp1 function. Epistasis analysis supports models in which Cbp1 functions coordinately with calcineurin to direct hyphal elongation during mating. Taken together, these findings provide insights into the roles of Cbp1 as an accessory subunit or effector of calcineurin-specific signaling pathways, which may be features conserved among the calcipressins to govern calcineurin signaling in immune cells, cardiomyocytes, and neurons of multicellular eukaryotes.

* Corresponding author. Mailing address for D. Fox: Research Institute for Children and Department of Pediatrics, Louisiana State Health Science Center, Children's Hospital, 200 Henry Clay Avenue, New Orleans, LA 70118. Phone: 504-986-2766. Fax: 504-986-2766. E-mail: dfox{at}chnola-research.org. Mailing address for J. Heitman: Department of Molecular Genetics and Microbiology, Duke University Medical Center, 322 CARL Building, Research Drive, Box 3546, Durham, NC 27710. E-mail: heitm001{at}duke.edu.

Eukaryotic Cell, September 2005, p. 1526-1538, Vol. 4, No. 9
1535-9778/05/$08.00+0     doi:10.1128/EC.4.9.1526-1538.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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