Ubiquitin proteolysis of a CDK-related kinase regulates titan cell formation and virulence in the fungal pathogen Cryptococcus neoformans
Open accessAbstract
Fungal pathogens often undergo morphological switches, including cell size changes, to adapt to the host environment and cause disease. The pathogenic yeast Cryptococcus neoformans forms so-called ‘titan cells’ during infection. Titan cells are large, polyploid, display alterations in cell wall and capsule, and are more resistant to phagocytosis and various types of stress. Titan cell formation is regulated by the cAMP/PKA signal pathway, which is stimulated by the protein Gpa1. Here, we show that Gpa1 is activated through phosphorylation by a CDK-related kinase (Crk1), which is targeted for degradation by an E3 ubiquitin ligase (Fbp1). Strains overexpressing CRK1 or an allele lacking a PEST domain exhibit increased production of titan cells similarly to the fbp1∆ mutant. Conversely, CRK1 deletion results in reduced titan cell production, indicating that Crk1 stimulates titan cell formation. Crk1 phosphorylates Gpa1, which then localizes to the plasma membrane and activates the cAMP/PKA signal pathway to induce cell enlargement. Furthermore, titan cell-overproducing strains trigger increased Th1 and Th17 cytokine production in CD4+ T cells and show attenuated virulence in a mouse model of systemic cryptococcosis. Overall, our study provides insights into the regulation of titan cell formation and fungal virulence.
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One mechanism of C. neoformans heteroresistance is associated with multiple types of aneuploid daughter cells produced by titan cells.
“One of its mechanisms is associated with the multiple types of aneuploid daughter cells produced by titan cells [56,140,141].”
From Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance (2025) · cites this paper as [140]
The Introduction (page not provided) says titan cells produce haploid or aneuploid daughter cells that are better adapted to host stressors. It does not link those daughters to heteroresistance or describe multiple types of aneuploid daughter cells. (LLM, conf=0.84)
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Insight into the Mechanisms and Clinical Relevance of Antifungal Heteroresistance
Su, Y., Li, Y., Yi, Q., Xu, Y., Sun, T., & Li, Y. (2025) · Journal of Fungi · doi:10.3390/jof11020143 · Cited by 18 · see citing works
“One of its mechanisms is associated with the multiple types of aneuploid daughter cells produced by titan cells [56,140,141].”
- Authors
- Cao, C., Wang, K., Wang, Y., Liu, T.-B., Rivera, A., & Xue, C.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Xue, Chaoyang
- Venue
- Nature Communications
- Published
- 2022-10-27
- Volume
- 13
- Issue
- 1
- Pages
- 6397-6397
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC9613880
- OpenAlex
- W4307775136
- Cited by
- 18
- References
- 87
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 4 · 2022: 1
- FWCI
- 1.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Health
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (R01AI141368)
- Rutgers, The State University of New Jersey (HealthAdvance fund)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01AI123315)
- Topics
- Health Sciences › Medicine › Epidemiology › 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
- Cryptococcus neoformans, titan cells, GPA1, cAMP/PKA signaling, PEST domain, cell expansion, morphological switching, fungal virulence, cryptococcosis, CD4+ T cells, polyploidy
- MeSH terms
- Animals, Cryptococcosis, Cryptococcus neoformans, Fungal Proteins, Phosphorylation, Saccharomyces cerevisiae, Virulence, Ubiquitin, Mice, Proteolysis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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