Cryptococcal titan cell formation is regulated by G-protein signaling in response to multiple stimuli

Laura H Okagaki, Yina Wang, Elizabeth R Ballou, Teresa R O'Meara, Yong-Sun Bahn, J Andrew Alspaugh, Chaoyang Xue, Kirsten Nielsen

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1306-16
Number of pages11
JournalEukaryotic Cell
Issue number10
Publication statusPublished - Oct 2011
Externally publishedYes


  • Animals
  • Cryptococcosis
  • Cryptococcus neoformans
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Female
  • Fungal Proteins
  • GTP-Binding Proteins
  • Humans
  • Mice
  • Signal Transduction
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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