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Eukaryotic Cell, December 2005, p. 1971-1981, Vol. 4, No. 12
1535-9778/05/$08.00+0     doi:10.1128/EC.4.12.1971-1981.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pde1 Phosphodiesterase Modulates Cyclic AMP Levels through a Protein Kinase A-Mediated Negative Feedback Loop in Cryptococcus neoformans

Julie K. Hicks,1 Yong-Sun Bahn,1 and Joseph Heitman1,2,3*

Departments of Molecular Genetics and Microbiology,1 Medicine,2 Pharmacology and Cancer Biology,3 Duke University Medical Center, Durham, North Carolina 277104

Received 25 July 2005/ Accepted 20 September 2005

The virulence of the human pathogenic fungus Cryptococcus neoformans is regulated by a cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling cascade that promotes mating and the production of melanin and capsule. In this study, genes encoding homologs of the Saccharomyces cerevisiae low- and high-affinity phosphodiesterases, PDE1 and PDE2, respectively, were deleted in serotype A strains of C. neoformans. The resulting mutants exhibited moderately elevated levels of melanin and capsule production relative to the wild type. Epistasis experiments indicate that Pde1 functions downstream of the G{alpha} subunit Gpa1, which initiates cAMP-dependent signaling in response to an extracellular signal. Previous work has shown that the PKA catalytic subunit Pka1 governs cAMP levels via a negative feedback loop. Here we show that a pde1{Delta} pka1{Delta} mutant strain exhibits cAMP levels that are dramatically increased (~15-fold) relative to those in a pka1{Delta} single mutant strain and that a site-directed mutation in a consensus PKA phosphorylation site reduces Pde1 function. These data provide evidence that fluctuations in cAMP levels are modulated by both Pka1-dependent regulation of Pde1 and another target that comprise a robust negative feedback loop to tightly constrain intracellular cAMP levels.

* Corresponding author. Mailing address: Department of Molecular Genetics and Microbiology, 322 CARL Bldg., Duke University Medical Center, Research Dr., Durham, NC 27710. Phone: (919) 684-2824. Fax: (919) 684-5458. E-mail: heitm001{at}duke.edu.

Eukaryotic Cell, December 2005, p. 1971-1981, Vol. 4, No. 12
1535-9778/05/$08.00+0     doi:10.1128/EC.4.12.1971-1981.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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