title: Cryptococcal titan cell formation is regulated by G-protein signaling in response to multiple stimuli.
abstract: The titan cell is a recently described morphological form of the pathogenic fungus Cryptococcus neoformans. Occurring during the earliest stages of lung infection, titan cells are 5 to 10 times larger than the normal yeast-like cells, thereby resisting engulfment by lung phagocytes and favoring the persistence of infection. These enlarged cells exhibit an altered capsule structure, a thickened cell wall, increased ploidy, and resistance to nitrosative and oxidative stresses. We demonstrate that two G-protein-coupled receptors are important for induction of the titan cell phenotype: the Ste3a pheromone receptor (in mating type a cells) and the Gpr5 protein. Both receptors control titan cell formation through elements of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. This conserved signaling pathway, in turn, mediates its effect on titan cells through the PKA-regulated Rim101 transcription factor. Additional downstream effectors required for titan cell formation include the G(1) cyclin Pcl103, the Rho104 GTPase, and two GTPase-activating proteins, Gap1 and Cnc1560. These observations support developing models in which the PKA signaling pathway coordinately regulates many virulence-associated phenotypes in diverse human pathogens.
authors.affiliation: Department of Microbiology, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Okagaki
authors.forename: Yina
authors.initials: Y
authors.lastname: Wang
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Ballou
authors.forename: Teresa R
authors.initials: TR
authors.lastname: O'Meara
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Alspaugh
authors.forename: Chaoyang
authors.initials: C
authors.lastname: Xue
authors.forename: Kirsten
authors.initials: K
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D003453:Cryptococcosis / Q000382:microbiology*; D003455:Cryptococcus neoformans / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015398:Signal Transduction
chemical_list: D005656:Fungal Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins