Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

doi:10.1128/MCB.21.9.3179-3191.2001

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Molecular and Cellular Biology, May 2001, p. 3179-3191, Vol. 21, No. 9
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.9.3179-3191.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cyclic AMP-Dependent Protein Kinase Controls Virulence of the Fungal Pathogen Cryptococcus neoformans

Cletus A. D'Souza,¹ J. Andrew Alspaugh,¹^,² Changli Yue,¹ Toshiaki Harashima,¹^,³ Gary M. Cox,²^,⁴ John R. Perfect,²^,⁴ and Joseph Heitman¹^,²^,³^,⁴^,⁵^,^*

Departments of Genetics,¹ Medicine,² Microbiology,⁴ and Pharmacology and Cancer Biology,⁵ and Howard Hughes Medical Institute,³ Duke University Medical Center, Durham, North Carolina 27710

Received 3 November 2000/Returned for modification 5 December 2000/Accepted 29 January 2001

Cryptococcus neoformans is an opportunistic fungal pathogen that infects the human central nervous system. This pathogen elaboratestwo specialized virulence factors: the antioxidant melanin andan antiphagocytic immunosuppressive polysaccharide capsule. Asignaling cascade controlling mating and virulence was identified.The PKA1 gene encoding the major cyclic AMP (cAMP)-dependent proteinkinase catalytic subunit was identified and disrupted. pka1 mutantstrains were sterile, failed to produce melanin or capsule, andwere avirulent. The PKR1 gene encoding the protein kinase A (PKA)regulatory subunit was also identified and disrupted. pkr1 mutantstrains overproduced capsule and were hypervirulent in animalmodels of cryptococcosis. pkr1 pka1 double mutant strains exhibitedphenotypes similar to that of pka1 mutants, providing epistasisevidence that the Pka1 catalytic subunit functions downstreamof the Pkr1 regulatory subunit. The PKA pathway was also shownto function downstream of the G $alpha$ protein Gpa1 and to regulatecAMP production by feedback inhibition. These findings definea G $alpha$ protein-cAMP-PKA signaling pathway regulating differentiationand virulence of a human fungalpathogen.

^* Corresponding author. Mailing address: Department of Genetics, 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.

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