Calcineurin: The Achilles’ heel of fungal pathogens

Yadav, Vikas; Heitman, Joseph

doi:10.1371/journal.ppat.1011445

Cited by 9 publications

(3 citation statements)

References 42 publications

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“…We found that deletion of PP2A catalytic and regulatory subunits, PPH22 and FAR8, also led to an inability to grow at elevated temperatures or in the presence of FK506 or CsA at 30°C, suggesting a synthetic lethal relationship with calcineurin inhibition. In fungal pathogens, calcineurin also plays key roles in host temperature tolerance, sexual development, morphological transitions, cell wall integrity, drug tolerance, and ER stress response [62]. It is possible that PP2A and calcineurin share some overlapping functions by dephosphorylating common targets, with one phosphatase partially compensating for the other's loss.…”

Section: Neoformansmentioning

confidence: 99%

TheCryptococcus neoformansSTRIPAK complex controls genome stability, sexual development, and virulence

Peterson,

Choi,

et al. 2024

Preprint

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The eukaryotic serine/threonine protein phosphatase PP2A is a heterotrimeric enzyme composed of a scaffold A subunit, a regulatory B subunit, and a catalytic C subunit. Of the four known B subunits, the B’’’ subunit (known as striatin) interacts with the multi-protein striatin-interacting phosphatase and kinase (STRIPAK) complex. Orthologs of STRIPAK components were identified inC. neoformans, namely PP2AA/Tpd3, PP2AC/Pph22, PP2AB’’’/Far8, STRIP/Far11, SLMAP/Far9, and Mob3. Structural modeling, protein domain analysis, and detected protein-protein interactions suggestC. neoformansSTRIPAK is assembled similarly to the human and fungal orthologs. Here, STRIPAK components Pph22, Far8, and Mob3 were functionally characterized. Whole-genome sequencing revealed that mutations in STRIPAK complex subunits lead to increased segmental and chromosomal aneuploidy, suggesting STRIPAK functions in maintaining genome stability. We demonstrate thatPPH22is a haploinsufficient gene: heterozygousPPH22/pph22Δ mutant diploid strains exhibit defects in hyphal growth and sporulation and have a significant fitness disadvantage when grown in competition against a wild-type diploid. Deletion mutantspph22Δ,far8Δ, andmob3Δ exhibit defects in mating and sexual differentiation, including impaired hyphae, basidia, and basidiospore production. Loss of eitherPPH22orFAR8leads to growth defects at 30⁰C, severely reduced growth at elevated temperature, abnormal cell morphology, and impaired virulence. Thepph22Δ andfar8Δ mutants are also unable to grow in the presence of the calcineurin inhibitors cyclosporine A or FK506, and thus these mutations are synthetically lethal with loss of calcineurin activity. Conversely,mob3Δ mutants display increased thermotolerance, capsule production, and melanization, and are hypervirulent in a murine infection model. Taken together, these findings reveal that theC. neoformansSTRIPAK complex plays an important role in genome stability, vegetative growth, sexual development, and virulence in this prominent human fungal pathogen.

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Section: Neoformansmentioning

confidence: 99%

TheCryptococcus neoformansSTRIPAK complex controls genome stability, sexual development, and virulence

Peterson,

Choi,

et al. 2024

Preprint

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“…Calcineurin also promotes resistance and tolerance in pathogenic fungi to several different classes of antifungals ( 17 , 18 ). For example, calcineurin activation and signaling promote tolerance (also called cell viability) during long-term exposure of yeasts to azole-class antifungals, which target ergosterol biosynthesis in the endoplasmic reticulum (ER) ( 19 – 21 ).…”

Section: Introductionmentioning

confidence: 99%

“…Several other known substrates of calcineurin in the model yeast S. cerevisiae were also not required for calcineurin-dependent cell survival in response to ER stress ( 23 ) and the molecular mechanisms by which calcineurin promotes tolerance remain unknown. Calcineurin and Crz1 activation also promote echinocandin resistance by increasing the expression of FKS2 encoding a target of these drugs ( 17 , 18 ). Echinocandin resistance often arises through mutations within the coding sequences of FKS genes ( 24 , 25 ) although evidence suggests other pathways can contribute ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

Calcineurin-dependent contributions to fitness in the opportunistic pathogen Candida glabrata

Pavesic,

Gale,

Nickels

et al. 2024

mSphere

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The protein phosphatase calcineurin is vital for the virulence of the opportunistic fungal pathogen Candida glabrata . The host-induced stresses that activate calcineurin signaling are unknown, as are the targets of calcineurin relevant to virulence. To potentially shed light on these processes, millions of transposon insertion mutants throughout the genome of C. glabrata were profiled en masse for fitness defects in the presence of FK506, a specific inhibitor of calcineurin. Eighty-seven specific gene deficiencies depended on calcineurin signaling for full viability in vitro both in wild-type and pdr1∆ null strains lacking pleiotropic drug resistance. Three genes involved in cell wall biosynthesis ( FKS1 , DCW1 , FLC1 ) possess co-essential paralogs whose expression depended on calcineurin and Crz1 in response to micafungin, a clinical antifungal that interferes with cell wall biogenesis. Interestingly, 80% of the FK506-sensitive mutants were deficient in different aspects of vesicular trafficking, such as endocytosis, exocytosis, sorting, and biogenesis of secretory proteins in the endoplasmic reticulum (ER). In response to the experimental antifungal manogepix that blocks GPI-anchor biosynthesis in the ER, calcineurin signaling increased and strongly prevented cell death independent of Crz1, one of its major targets. Comparisons between manogepix, micafungin, and the ER-stressing tunicamycin reveal a correlation between the degree of calcineurin signaling and the degree of cell survival. These findings suggest that calcineurin plays major roles in mitigating stresses of vesicular trafficking. Such stresses may arise during host infection and in response to antifungal therapies. IMPORTANCE Calcineurin plays critical roles in the virulence of most pathogenic fungi. This study sheds light on those roles in the opportunistic pathogen Candida glabrata using a genome-wide analysis in vitro . The findings could lead to antifungal developments that also avoid immunosuppression.

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Calcineurin activity in Fonsecaea pedrosoi: tacrolimus and cyclosporine A inhibited conidia growth, filamentation and showed synergism with itraconazole

Sousa,

Tavares,

Silva

et al. 2024

Braz J Microbiol

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Calcineurin: The Achilles’ heel of fungal pathogens

Cited by 9 publications

References 42 publications

TheCryptococcus neoformansSTRIPAK complex controls genome stability, sexual development, and virulence

TheCryptococcus neoformansSTRIPAK complex controls genome stability, sexual development, and virulence

Calcineurin-dependent contributions to fitness in the opportunistic pathogen Candida glabrata

Calcineurin activity in Fonsecaea pedrosoi: tacrolimus and cyclosporine A inhibited conidia growth, filamentation and showed synergism with itraconazole

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