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Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli
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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 Ste3 a 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.
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“The titan cell also plays a key part in stress adaptation and resistance to antifungal drugs26,150.”
From Treatment strategies for cryptococcal infection: challenges, advances and future outlook (2021) · cites this paper as [150]
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Metadata
- Authors
- Okagaki, L. H., Wang, Y., Ballou, E. R., O'Meara, T. R., Bahn, Y.-S., Alspaugh, J. A., Xue, C., & Nielsen, K.
- Affiliations
- University of Minnesota (US)
- University of Medicine and Dentistry of New Jersey (US)
- Duke University (US)
- Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Yonsei University (KR)
- Corresponding author
- Nielsen, Kirsten
- Venue
- Eukaryotic Cell
- Publisher
- American Society for Microbiology
- Published
- 2011-10
- Volume
- 10
- Issue
- 10
- Pages
- 1306-1316
- ISSN
- 1535-9778 (ISSN-L)
- 1535-9786
- PMC
- PMC3187071
- OpenAlex
- W2104794604
- Cited by
- 117
- References
- 53
- Citations by year
- 2026: 12 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 12 · 2021: 7 · 2020: 5 · 2019: 8 · 2018: 10 · 2017: 7 · 2016: 4 · 2015: 8 · 2014: 9 · 2013: 9 · 2012: 12
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Eukaryotic Cell (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1f33ai008027-01)
- National Institute of Allergy and Infectious Diseases (R56AI074677, R01AI050128, AI089244, R01AI080275, AI08027, AI074677, AI070152, R01AI074677, U01AI089244, K22AI070152, AI050158)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Keywords
- titan cells, Cryptococcus neoformans, G protein signaling, G protein-coupled receptors, GTPase-activating protein, GAP1, fungal virulence, pulmonary infection, cell wall thickening, ploidy, oxidative stress resistance
- MeSH terms
- Cyclic AMP, Animals, Cryptococcosis, Cryptococcus neoformans, Female, Fungal Proteins, Humans, Signal Transduction, Cyclic AMP-Dependent Protein Kinases, GTP-Binding Proteins, Mice
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