ArticleMolecular and cellular biology1999
Rapamycin antifungal action is mediated via conserved complexes with FKBP12 and TOR kinase homologs in Cryptococcus neoformans.
Article in Molecular and cellular biology, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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Who cites it
79 citing papers in PubMed, 185 citations in OpenAlex.
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- Drug to genome to drug: a computational large-scale chemogenomics screening for novel drug candidates against sporotrichosis.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2024Article
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- Resolving the Temporal Splenic Proteome during Fungal Infection for Discovery of Putative Dual Perspective Biomarker Signatures.Journal of the American Society for Mass Spectrometry · 2023Article
- Expression of mTOR in normal and pathological conditions.Molecular cancer · 2023Review
- Fungal resilience and host-pathogen interactions: Future perspectives and opportunities.Parasite immunology · 2023Review
- Genome-wide analysis of heat stress-stimulated transposon mobility in the human fungal pathogenProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Drug Target Elucidation Through Isolation and Analysis of Drug-Resistant Mutants in Cryptococcus neoformans.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Interactions between antifungals and everolimus againstFrontiers in cellular and infection microbiology · 2023Article
- Natural product ligands of FKBP12: Immunosuppressive antifungal agents FK506, rapamycin, and beyond.PLoS pathogens · 2023Article
- Stress- and metabolic responses of Candida albicans require Tor1 kinase N-terminal HEAT repeats.PLoS pathogens · 2022Article
- Cyclic Tetrapeptides with Synergistic Antifungal Activity from the FungusAntibiotics (Basel, Switzerland) · 2022Article
- Intracerebral opportunistic infections caused by immunosuppressants after orthotopic liver transplantation: Report of two cases and literature review.Frontiers in immunology · 2022Review
- High-dose rapamycin exerts a temporary impact on T. reesei RUT-C30 through gene trFKBP12.Biotechnology for biofuels · 2021Article
- Target of Rapamycin in Control of Autophagy: Puppet Master and Signal Integrator.International journal of molecular sciences · 2020Review
- Structure-guided approaches to targeting stress responses in human fungal pathogens.The Journal of biological chemistry · 2020Review
19 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Cryptococcus neoformans is a fungal pathogen that causes meningitis in patients immunocompromised by AIDS, chemotherapy, organ transplantation, or high-dose steroids. Current antifungal drug therapies are limited and suffer from toxic side effects and drug resistance. Here, we defined the targets and mechanisms of antifungal action of the immunosuppressant rapamycin in C. neoformans. In the yeast Saccharomyces cerevisiae and in T cells, rapamycin forms complexes with the FKBP12 prolyl isomerase that block cell cycle progression by inhibiting the TOR kinases. We identified the gene encoding a C. neoformans TOR1 homolog. Using a novel two-hybrid screen for rapamycin-dependent TOR-binding proteins, we identified the C. neoformans FKBP12 homolog, encoded by the FRR1 gene. Disruption of the FKBP12 gene conferred rapamycin and FK506 resistance but had no effect on growth, differentiation, or virulence of C. neoformans. Two spontaneous mutations that confer rapamycin resistance alter conserved residues on TOR1 or FKBP12 that are required for FKBP12-rapamycin-TOR1 interactions or FKBP12 stability. Two other spontaneous mutations result from insertion of novel DNA sequences into the FKBP12 gene. Our observations reveal that the antifungal activities of rapamycin and FK506 are mediated via FKBP12 and TOR homologs and that a high proportion of spontaneous mutants in C. neoformans result from insertion of novel DNA sequences, and they suggest that nonimmunosuppressive rapamycin analogs have potential as antifungal agents.
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