title: Adenylyl cyclase-associated protein Aca1 regulates virulence and differentiation of Cryptococcus neoformans via the cyclic AMP-protein kinase A cascade.
abstract: The evolutionarily conserved cyclic AMP (cAMP) signaling pathway controls cell functions in response to environmental cues in organisms as diverse as yeast and mammals. In the basidiomycetous human pathogenic fungus Cryptococcus neoformans, the cAMP pathway governs virulence and morphological differentiation. Here we identified and characterized adenylyl cyclase-associated protein, Aca1, which functions in parallel with the Galpha subunit Gpa1 to control the adenylyl cyclase (Cac1). Aca1 interacted with the C terminus of Cac1 in the yeast two-hybrid system. By molecular and genetic approaches, Aca1 was shown to play a critical role in mating by regulating cell fusion and filamentous growth in a cAMP-dependent manner. Aca1 also regulates melanin and capsule production via the Cac1-cAMP-protein kinase A pathway. Genetic epistasis studies support models in which Aca1 and Gpa1 are necessary and sufficient components that cooperate to activate adenylyl cyclase. Taken together, these studies further define the cAMP signaling cascade controlling virulence of this ubiquitous human fungal pathogen.
authors.affiliation: Department of Molecular Genetics and Microbiology, 322 CARL Bldg., Box 3546, Research Dr., Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
authors.forename: Julie K
authors.initials: JK
authors.lastname: Hicks
authors.forename: Steven S
authors.initials: SS
authors.lastname: Giles
authors.forename: Gary M
authors.initials: GM
authors.lastname: Cox
authors.forename: Joseph
authors.initials: J
authors.lastname: Heitman
mesh_terms: D051696:Activating Transcription Factors; D000595:Amino Acid Sequence; D003455:Cryptococcus neoformans / Q000472:pathogenicity* / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005091:Exons; D005838:Genotype; D008543:Melanins / Q000378:metabolism; D008954:Models, Biological; D008957:Models, Genetic; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D020798:Two-Hybrid System Techniques
chemical_list: C410227:ACA1 protein, S cerevisiae; D051696:Activating Transcription Factors; D008543:Melanins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases