Calcineurin regulatory subunit is essential for virulence and mediates interactions with FKBP12–FK506 in Cryptococcus neoformans
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Calcineurin is a Ca 2+–calmodulin‐regulated protein phosphatase that is the target of the immunosuppressive drugs cyclosporin A and FK506. Calcineurin is a heterodimer composed of a catalytic A and a regulatory B subunit. In previous studies, the calcineurin A homologue was identified and shown to be required for growth at 37°C and hence for virulence of the pathogenic fungus Cryptococcus neoformans. Here, we identify the gene encoding the calcineurin B regulatory subunit and demonstrate that calcineurin B is also required for growth at elevated temperature and virulence. We show that the FKR1‐1 mutation, which confers dominant FK506 resistance, results from a 6 bp duplication generating a two‐amino‐acid insertion in the latch region of calcineurin B. This mutation was found to reduce FKBP12–FK506 binding to calcineurin both in vivo and in vitro. Molecular modelling based on the FKBP12–FK506–calcineurin crystal structure illustrates how this mutation perturbs drug interactions with the phosphatase target. In summary, our studies reveal a central role for calcineurin B in virulence and antifungal drug action in the human fungal pathogen C. neoformans.
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The C. glabrata Δcnb1 strain phenotype (increased susceptibility to azoles and cell wall-damaging agents, decreased virulence) is consistent with previous findings for other pathogenic fungi.
“For example, the observed C. glabrata Δcnb1 strain phenotype, which is characterized by an increased susceptibility to azoles and cell wall-damaging agents as well as decreased virulence, is consistent with previous findings for other pathogenic fungi, such as C. albicans (2-4, 27), C. neoformans (11, 18, 21), and A. fumigatus (9, 30).”
From Roles of Calcineurin and Crz1 in Antifungal Susceptibility and Virulence of <i>Candida glabrata</i> (2010) · cites this paper as [11]
Calcineurin is a bona fide client of Hsp90 and has been implicated in growth at high temperature and virulence of Cryptococcus.
“For example, calcineurin, a bona fide client of Hsp90, has been implicated in growth at high temperature as well as virulence of the pathogen [47–49].”
From Heat shock protein 90 localizes to the surface and augments virulence factors of Cryptococcus neoformans (2017) · cites this paper as [48]
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References 46 · Cited by 175
- Authors
- Fox, D. S., Cruz, M. C., Sia, R. A. L., Ke, H., Cox, G. M., Cardenas, M. E., & Heitman, J.
- Affiliations
- Duke University (US)
- University of North Carolina at Chapel Hill (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Heitman, Joseph
- Venue
- Molecular Microbiology
- Publisher
- Wiley
- Published
- 2001-02
- Volume
- 39
- Issue
- 4
- Pages
- 835-849
- ISSN
- 0950-382X (ISSN-L)
- 1365-2958
- OpenAlex
- W2147728137
- Cited by
- 175
- References
- 46
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 4 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 9 · 2019: 2 · 2018: 6 · 2017: 7 · 2016: 5 · 2015: 2 · 2014: 12 · 2013: 7 · 2012: 3
- FWCI
- 7.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Microbiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5u01ai047087-03)
- National Institute of Allergy and Infectious Diseases (U01AI47087, AI07392-10, R01AI039115, T32AI007392)
- Topics
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- calcineurin, Cryptococcus neoformans, virulence, cyclosporine, protein phosphatase, fungal pathogens
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cryptococcosis, Cryptococcus neoformans, Disease Models, Animal, DNA, Fungal, Fungal Proteins, Genes, Fungal, Heating, Humans, Mice, Inbred DBA, Molecular Sequence Data, Recombination, Genetic, Virulence, Mutagenesis, Tacrolimus, Sequence Homology, Amino Acid, Protein Structure, Secondary, Calcineurin, Tacrolimus Binding Protein 1A, Mice
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