title: Cryptococcus neoformans mating and virulence are regulated by the G-protein alpha subunit GPA1 and cAMP.
abstract: This study explores signal transduction pathways that function during mating and infection in the opportunistic, human fungal pathogen Cryptococcus neoformans. The gene encoding a G-protein alpha subunit homolog, GPA1, was disrupted by homologous recombination. The gpa1 mutant strain was viable but exhibited a defect in mating in response to nitrogen starvation. Additionally, the gpa1 mutant strain failed to induce two well-established virulence factors-melanin synthesis, in response to glucose starvation; and capsule production, in response to iron limitation. As a consequence, virulence of the gpa1 mutant strain was significantly attenuated in an animal model of cryptococcal meningitis. Reintroduction of the wild-type GPA1 gene complemented the gpa1 mutant phenotypes and restored mating, melanin and capsule production, and virulence. Similarly, exogenous cAMP also suppressed the gpa1 mutant phenotypes, restoring mating and production of melanin and capsule. These observations support a model in which GPA1 has a role in sensing diverse environmental signals required for mating and virulence by regulating cAMP metabolism in C. neoformans.
authors.affiliation: Department of Genetics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Alspaugh
authors.forename: J R
authors.initials: JR
authors.lastname: Perfect
authors.forename: J
authors.initials: J
authors.lastname: Heitman
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000134:cerebrospinal fluid / Q000382:microbiology; D003455:Cryptococcus neoformans / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D000242:Cyclic AMP / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005800:Genes, Fungal; D020962:Heterotrimeric GTP-Binding Proteins; D006801:Humans; D008297:Male; D008543:Melanins / Q000096:biosynthesis; D016921:Meningitis, Fungal / Q000134:cerebrospinal fluid / Q000382:microbiology; D016296:Mutagenesis; D010641:Phenotype; D011817:Rabbits; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014774:Virulence / Q000235:genetics
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D008543:Melanins; D029701:Saccharomyces cerevisiae Proteins; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; C084293:GPA1 protein, S cerevisiae; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins