Two cyclophilin A homologs with shared and distinct functions important for growth and virulence of Cryptococcus neoformans.
Cyclophilin A is the target of the immunosuppressant cyclosporin A (CsA) and is encoded by a single unique gene conserved from yeast to humans. In the pathogenic fungus Cryptococcus neoformans, two homologous linked genes, CPA1 and CPA2, were found to encode two conserved cyclophilin A proteins. In contrast to Saccharomyces cerevisiae, in which cyclophilin A mutations confer CsA resistance but few other phenotypes, cyclophilin A mutations conferred dramatic phenotypes in C. neoformans. The Cpa1 and Cpa2 cyclophilin A proteins play a shared role in cell growth, mating, virulence and CsA toxicity. The Cpa1 and Cpa2 proteins also have divergent functions. cpa1 mutants are inviable at 39 degrees C and attenuated for virulence, whereas cpa2 mutants are viable at 39 degrees C and fully virulent. cpa1 cpa2 double mutants exhibited synthetic defects in growth and virulence. Cyclophilin A active site mutants restored growth of cpa1 cpa2 mutants at ambient but not at higher temperatures, suggesting that the prolyl isomerase activity of cyclophilin A has an in vivo function.
Wang
P
P
Departments of Genetics, Duke University Medical Center, Durham, NC 27710, USA.
Cardenas
M E
ME
Cox
G M
GM
Perfect
J R
JR
Heitman
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D015139:Blotting, Southern; D003455:Cryptococcus neoformans / Q000378:metabolism* / Q000472:pathogenicity; D021984:Cyclophilin A / Q000737:chemistry* / Q000235:genetics* / Q000502:physiology; D005260:Female; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010641:Phenotype; D011817:Rabbits; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D013997:Time Factors; D014774:Virulence
D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase