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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
elaborates two specialized virulence factors: the antioxidant melanin
and an antiphagocytic immunosuppressive polysaccharide capsule. A signaling cascade controlling mating and virulence was identified. The
PKA1 gene encoding the major cyclic AMP (cAMP)-dependent
protein kinase catalytic subunit was identified and disrupted.
pka1 mutant strains were sterile, failed to produce melanin
or capsule, and were avirulent. The PKR1 gene encoding the
protein kinase A (PKA) regulatory subunit was also identified and
disrupted. pkr1 mutant strains overproduced capsule and
were hypervirulent in animal models of cryptococcosis. pkr1
pka1 double mutant strains exhibited phenotypes similar to that
of pka1 mutants, providing epistasis evidence that the Pka1
catalytic subunit functions downstream of the Pkr1 regulatory subunit.
The PKA pathway was also shown to function downstream of the G
protein Gpa1 and to regulate cAMP production by feedback inhibition.
These findings define a G
protein-cAMP-PKA signaling pathway
regulating differentiation and virulence of a human fungal pathogen.
*
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.
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.
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