Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 21, Issue 9, Pages 3179-3191Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.21.9.3179-3191.2001
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Funding
- NIAID NIH HHS [R37 AI039115, R01 AI042159, R01 AI42159, R01 AI039115, R01 AI39115, K08 AI01556, P01 AI044975, P01 AI44975] Funding Source: Medline
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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 submit 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 alpha protein Gpa1 and to regulate cAMP production by feedback inhibition. These findings define a G alpha protein-cAMP-PKA signaling pathway regulating differentiation and virulence of a human fungal pathogen.
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