Cited by 117Fungal Infections and StudiesFungal and yeast genetics researchAntifungal resistance and susceptibility

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Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli

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Okagaki, Laura H., Wang, Yina, Ballou, Elizabeth R., O'Meara, Teresa R., Bahn, Yong-Sun, Alspaugh, J. Andrew, Xue, Chaoyang, Nielsen, Kirsten·2011·Eukaryotic Cell

DOI 10.1128/ec.05179-11PMC PMC3187071

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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 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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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
ORCID: Wang, Yina
Ballou, Elizabeth R.
Bahn, Yong-Sun
Alspaugh, J. Andrew
Xue, Chaoyang
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
DOI: 10.1128/ec.05179-11
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
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
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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Cryptococcal Titan Cell Formation Is Regulated by G-Protein Signaling in Response to Multiple Stimuli

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