Cyclic AMP-dependent protein kinase controls virulence of the fungal pathogen Cryptococcus neoformans

被引:262
作者
D'Souza, CA
Alspaugh, JA
Yue, CL
Harashima, T
Cox, GM
Perfect, JR
Heitman, J
机构
[1] Duke Univ, Med Ctr, Dept Genet, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Dept Microbiol, Durham, NC 27710 USA
[4] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA
[5] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA
关键词
D O I
10.1128/MCB.21.9.3179-3191.2001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:3179 / 3191
页数:13
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