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Cited by 117Fungal and yeast genetics researchAntifungal resistance and susceptibilitySignaling Pathways in Disease

Calcineurin as a multifunctional regulator: Unraveling novel functions in fungal stress responses, hyphal growth, drug resistance, and pathogenesis

Open access
Juvvadi, Praveen R., Lamoth, Frédéric, Steinbach, William J.·2014·Fungal Biology Reviews
DOI 10.1016/j.fbr.2014.02.004PMC PMC4219591
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Abstract

Calcineurin signaling plays diverse roles in fungi in regulating stress responses, morphogenesis and pathogenesis. Although calcineurin signaling is conserved among fungi, recent studies indicate important divergences in calcineurin-dependent cellular functions among different human fungal pathogens. Fungal pathogens utilize the calcineurin pathway to effectively survive the host environment and cause life-threatening infections. The immunosuppressive calcineurin inhibitors (FK506 and cyclosporine A) are active against fungi, making targeting calcineurin a promising antifungal drug development strategy. Here we summarize current knowledge on calcineurin in yeasts and filamentous fungi, and review the importance of understanding fungal-specific attributes of calcineurin to decipher fungal pathogenesis and develop novel antifungal therapeutic approaches.

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Written from the paper’s full text.

TL;DR

This review synthesizes the state of knowledge on calcineurin signaling in fungi, arguing that although the pathway is conserved, its downstream functions diverge substantially among human fungal pathogens. It highlights calcineurin as a promising antifungal target, particularly through the Hsp90–calcineurin–CrzA axis and a newly identified filamentous-fungal-specific phosphorylation domain.

Key findings

  • Calcineurin is required for stress adaptation (alkaline pH, temperature, cation homeostasis), hyphal growth, cell wall integrity, and virulence, but its specific roles differ by species: the *C. neoformans* catalytic subunit disruption strain was avirulent and nonviable at 37°C/5% CO2/alkaline pH, whereas *C. albicans* calcineurin was dispensable at 37–42°C and its *cnb1* mutant still showed filamentous growth in vivo yet failed to grow in a mouse model of disseminated candidiasis and could not survive in serum.
  • In *A. fumigatus*, the calcineurin complex (CnaA/CnaB) localizes to hyphal tips and septa; deletion mutants had thicker cell walls and abnormal septa, and loss of calcineurin produced a compensatory increase in chitin content in response to reduced β-1,3-glucan biosynthesis — a basis for proposed combination therapy targeting calcineurin, β-1,3-glucan, and chitin.
  • A novel filamentous-fungal-specific "Serine Proline Rich Region" (SPRR) between the CnBBH and CaMBD was identified in CnaA; it was phosphorylated at all 4 clustered serine residues, and mutations there caused hyphal growth and virulence defects. FK506 treatment reduced phosphorylation of specific serine residues in CnaA SPRR and CnaB, revealing a new mode of calcineurin inhibition.
  • Hsp90 stabilizes calcineurin and mediates azole/echinocandin resistance; calcineurin inhibition phenocopies Hsp90 inhibition. In *A. fumigatus*, a 100-bp proximal *hsp90* promoter sequence containing two putative CDRE elements was required for a 1.5-fold increase in *hsp90* expression needed for the caspofungin paradoxical effect.

Methods

  • Narrative literature review summarizing current knowledge on calcineurin in yeasts (*S. cerevisiae*, *S. pombe*, *C. albicans*, *C. neoformans*) and filamentous fungi (*A. nidulans*, *A. fumigatus*, *N. crassa*, *M. oryzae*, *B. cinerea*, *Ustilago* spp., *S. sclerotiorum*), with emphasis on the authors' own work on *A. fumigatus*.
  • No primary experimental data are reported; the review integrates published genetic, phenotypic, localization, and drug-interaction studies, including the authors' structural modeling and in vitro phosphorylation assays identifying GSK3β, CK1, CDK1, and MAPK as candidate CnaA kinases.

Limitations

  • The paper states that mechanisms of calcineurin control of hyphal growth and development "remain less well characterized," and that knowledge of calcineurin's posttranscriptional roles and interacting proteins is limited.
  • It notes that current calcineurin inhibitors (CsA, FK506) are not ideal antifungals due to immunosuppression from host calcineurin cross-reactivity, and that the single murine invasive aspergillosis study of CsA/FK506/sirolimus "was not conclusive."
  • Evident from the text (not stated as a limitation by the authors): this is a narrative review without systematic search or quantitative synthesis, and several key conclusions rest on the authors' own *A. fumigatus* studies, so generalizability across fungal pathogens is explicitly cautioned against by the authors themselves.

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Registry

Crossref · 10.1016/j.fbr.2014.02.004

Cites

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Statistics

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Claims the paper makes

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  • Findingcitation

    We recently identified a filamentous fungal-specific novel linker domain between the CnBBH and the CaMBD, designated the Serine Proline Rich Region (SPRR).

    “During the course of analyzing the various conserved regions in CnaA, we recently identified a filamentous fungal-specific novel linker domain between the CnBBH and the CaMBD which we designated as the “Serine Proline Rich Region (SPRR)” (Juvvadi et al., 2013).”
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  • Findingown data

    The SPRR region was phosphorylated at all 4 clustered serine residues.

    “This SPRR region was phosphorylated at all 4 clustered serine residues.”
    Quote in the paperSubstantial claim
  • Findingown data

    In vitro phosphorylation assays revealed GSK3β, CK1, CDK1 and MAPK as potential kinases that might phosphorylate CnaA in vivo.

    “In vitro phosphorylation assays revealed GSK3β, CK1, CDK1 and MAPK as potential kinases that might phosphorylate CnaA in vivo.”
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  • Premisecitation

    In C. albicans, calcineurin is required for growth at both alkaline and acidic pH.

    “In C. albicans, previous studies also revealed a novel requirement for calcineurin for growth at both alkaline and acidic pH (Bader et al., 2006; Kullas et al., 2007).”
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  • Interpretationreasoning

    Targeting calcineurin is a promising antifungal drug development strategy.

    “The immunosuppressive calcineurin inhibitors (FK506 and cyclosporine A) are active against fungi, making targeting calcineurin a promising antifungal drug development strategy.”
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    Findingown data

    Heterologous expression of CnaA homologs from N. crassa and M. grisea revealed phosphorylation of serine residues within the SPRR, further evidence that filamentous fungal calcineurins have diverged from yeasts and other systems.

    “Heterologous expression of CnaA homologs from other closely related filamentous fungi, N. crassa and M. grisea, also revealed the phosphorylation of serine residues within the SPRR, further evidence that filamentous fungal calcineurins have diverged from the yeasts and other systems.”
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    Findingown data

    FK506 treatment caused reduction in phosphorylation of specific serine residues in CnaA SPRR and CnaB, revealing a new mode of calcineurin inhibition by FK506.

    “FK506 treatment caused reduction in phosphorylation of specific serine residues in CnaA SPRR and CnaB, revealing a new mode of calcineurin inhibition by FK506.”
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    Findingown data

    Mutations in the SPRR region did not affect septal localization of CnaA, but caused hyphal growth and virulence defects, implicating the importance of calcineurin phosphorylation for its function.

    “Though mutations in this region did not affect septal localization of CnaA, they caused hyphal growth and virulence defects, implicating the importance of calcineurin phosphorylation for its function.”
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    Findingown data

    A phylogenetic tree based on variable linker domain sequences and flanking conserved CnBBH and CaMBD sequences distinguished filamentous fungal calcineurins from other organisms, revealing the possibility of filamentous fungi acquiring this domain during evolution.

    “A phylogenic tree constructed based on the variable linker domain sequences and the flanking highly conserved CnBBH and CaMBD sequences from yeasts to human clearly distinguished the filamentous fungal calcineurins from other organisms based on this novel linker region, revealing the possibility of filamentous fungi acquiring this domain during evolution.”
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    Findingnone given

    In addition to the SPRR, CnaA was also phosphorylated at 2 serine residues at its C-terminus as well as at 2 serine residues in the CnaB N-terminus.

    “In addition to the SPRR, CnaA was also phosphorylated at 2 serine residues at its C-terminus as well as at 2 serine residues in the CnaB N-terminus.”
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    Premisecitation

    There is a growing population of drug resistant isolates of Cryptococcus, Candida, and Aspergillus species and recently emerging Zygomycete species Mucor circinelloides and Rhizopus oryzae.

    “There is a growing population of drug resistant isolates of Cryptococcus, Candida, and Aspergillus species (Cowen and Steinbach, 2008), and recently emerging Zygomycete species, Mucor circinelloides and Rhizopus oryzae (Shirazi and Kontoyiannis, 2013)”
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    Premisecitation

    Calcineurin is essential for fungal growth, stress responses, mating and pathogenesis.

    “the fact that calcineurin is essential for fungal growth, stress responses, mating and pathogenesis has generated great interest among medical mycologists (Bastidas et al., 2008; Chen et al., 2010).”
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    Premisecitation

    Crz1p exhibits permanent nuclear localization during illumination, different from its response to high extracellular Ca2+ levels.

    “In comparison to the oscillatory nuclear-cytoplasmic shuttling of the Msn2p and Msn4p transcription factors that are the major stress response regulators in the budding yeast (Estruch, 2000), Crz1p exhibited permanent nuclear localization, which is different than the previously reported response following exposure to high extracellular Ca2+ levels (Cai et al., 2008).”
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    Premisecitation

    The A. nidulans crzA mutant exhibited sensitivity to alkaline pH, high calcium and manganese concentrations, and mediated expression of P-type calcium-ATPase homologous genes.

    “Similarly, two independent investigations have revealed that the A. nidulans crzA (CRZ1 homolog) mutant exhibited sensitivity to alkaline pH, high calcium and manganese concentrations, and mediated the expression of P-type calcium-ATPase homologous genes (Hagiwara et al., 2008; Spielvogel et al., 2008).”
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    Premisecitation

    Calcineurin is the only phosphatase recognized in fungi that is regulated by Ca2+ and CaM.

    “Calcineurin is the only phosphatase recognized in fungi that is regulated by Ca2+ and CaM, and its principal target, Crz1 (homolog of NFAT), has also been well studied in Saccharomyces cerevisiae (Stathopoulos-Gerontides et al., 1999).”
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    Premisecitation

    The C. neoformans calcineurin catalytic subunit disruption strain was not viable in conditions mimicking the host environment (37°C, 5% CO2 or alkaline pH) and was avirulent.

    “While the S. cerevisiae calcineurin catalytic subunit null mutant was able to grow at higher temperature (Liu et al., 1991), the C. neoformans calcineurin catalytic subunit disruption strain was not viable in conditions that mimicked the host environment (37° C, 5% CO2 or alkaline pH) and was avirulent (Odom et al., 1997).”
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    Premisecitation

    Crz1p translocates into the nucleus and activates gene expression during illumination.

    “The calcineurin-dependent transcription factor, Crz1p, was shown to translocate into the nucleus and activate gene expression during illumination (Bodvard et al., 2013).”
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    Premisecitation

    The CRZ1 mutant did not exhibit sensitivity to alkaline pH, revealing that calcineurin may regulate pH stress response in a Crz1-independent manner by interacting with HPH1 and HPH2.

    “However, the CRZ1 mutant did not exhibit sensitivity to alkaline pH (Stathopoulos and Cyert, 1997), revealing that calcineurin may also regulate pH stress response in a Crz1-independent manner by interacting with other alkaline responsive genes, such as HPH1 and HPH2, which were reported as substrates of calcineurin (Heath et al., 2004).”
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    Premisenone given

    CsA and FK506 inhibit calcineurin by first binding to their respective intracellular receptors, cyclophilin A and FKBP12.

    “Drugs such as cyclosporin A (CsA) and tacrolimus (FK506) inhibit calcineurin function by first binding to their respective intracellular receptors, the immunophilins cyclophilin A (CyA) and FK506-binding protein (FKBP12).”
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    Premisecitation

    The C. albicans cnb1 mutant showed filamentous growth in vivo but failed to grow in a mouse model of disseminated candidiasis and was unable to survive in serum, revealing evolutionarily distinct control aspects of calcineurin over virulence of two divergent fungal pathogens via distinct mechanisms.

    “Although the C. albicans cnb1 mutant strain showed filamentous growth in vivo, it failed to grow in a mouse model of disseminated candidiasis and was unable to survive in serum, revealing evolutionarily distinct control aspects of calcineurin over virulence of two divergent fungal pathogens via distinct mechanisms (Blankenship and Heitman, 2005; Blankenship et al., 2003; Kraus et al., 2003).”
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    Premisecitation

    Calcineurin is a heterodimer consisting of an α-catalytic subunit calcineurin A (~60 kDa) that binds CaM and a regulatory β-subunit calcineurin B (~19 kDa).

    “It is a heterodimer consisting of two subunits, the α-catalytic subunit, termed calcineurin A (~60 kDa) that binds to CaM, and a regulatory β-subunit, termed calcineurin B (~19 kDa) (Rusnak and Mertz, 2000).”
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    Premisecitation

    Calcineurin homologs are widely distributed in parasites, fungi, plants, invertebrates and higher vertebrates.

    “Calcineurin homologs are widely distributed in different organisms, ranging from parasites, fungi, plants and invertebrates to the higher vertebrates (Naderer et al., 2011; Rusnak and Mertz, 2000; Singh et al., 2014).”
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    Premisecitation

    S. pombe and most other filamentous fungal species contain a single gene each encoding the catalytic and regulatory subunits of calcineurin.

    “S. pombe and most other filamentous fungal species contain a single gene each encoding the catalytic subunit and the regulatory subunit of calcineurin (Yoshida et al., 1994).”
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    Interpretationnone given

    Although calcineurin signaling is conserved among fungi, recent studies indicate important divergences in calcineurin-dependent cellular functions among different human fungal pathogens.

    “Although calcineurin signaling is conserved among fungi, recent studies indicate important divergences in calcineurin-dependent cellular functions among different human fungal pathogens.”
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    Premisecitation

    Constitutive expression of active calcineurin resulted in higher tolerance to toxic levels of Na+ and K+ by promoting ENA1 expression and resulted in elongated and unipolar budding, providing evidence for calcineurin control of polarity establishment.

    “Supporting these observations, constitutive expression of active calcineurin resulted in higher tolerance to even toxic levels of Na+ and K+ by promoting the expression of ENA1 and resulted in elongated and unipolar budding, providing evidence for calcineurin control of polarity establishment (Mendoza et al., 1996).”
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    Premisecitation

    Deletion of A. fumigatus crzA conferred a severe growth defect in increased calcium and manganese, decreased conidiation, abnormal conidial surface morphology, altered mRNA expression of calcium transporters and a virulence defect.

    “The deletion of A. fumigatus crzA also conferred a severe growth defect in the presence of increased concentrations of calcium and manganese, in addition to decreased conidiation, abnormal conidial surface morphology, altered mRNA expression of calcium transporters and a virulence defect (Cramer et al., 2008; Soriani et al., 2008).”
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    Premisecitation

    Calcineurin regulates growth at alkaline pH, elevated temperature, membrane stress and virulence in C. albicans and C. neoformans.

    “Calcineurin also regulates growth at alkaline pH, elevated temperature, membrane stress and virulence in the pathogenic yeasts Candida albicans and Cryptococcus neoformans (Chen et al., 2010; Kozubowski and Heitman, 2012).”
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    Premisecitation

    In contrast to C. neoformans, calcineurin is dispensable for survival of C. albicans at 37 or 42°C, and C. albicans cnb1 mutant strains had no defects in germination and filamentous growth.

    “In contrast to C. neoformans, calcineurin was dispensable for survival of C. albicans at 37 or 42° C, and the C. albicans cnb1 mutant strains had no defects in germination and filamentous growth (Blankenship et al., 2003).”
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    Premisenone given

    Knowledge on calcineurin's posttranscriptional roles and interacting proteins leading to regulation is limited.

    “yet knowledge on its posttranscriptional roles and interacting proteins leading to regulation is limited.”
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    Premisecitation

    In C. albicans, calcineurin is important for maintenance of colony morphology and dimorphic switching, and regulates downstream target genes including PMC1 and FKS1.

    “In C. albicans, calcineurin is also important for maintenance of colony morphology and dimorphic switching, in addition to regulating several downstream target genes, including PMC1, the vacuolar calcium P-type ATPase, and FKS1, the β-1,3 glucan synthase subunit (Sanglard et al., 2003).”
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    Premisecitation

    In S. cerevisiae, the calcineurin catalytic subunit is encoded by CNA1 and CNA2, and the regulatory subunit by CNB1.

    “In S. cerevisiae, the calcineurin catalytic subunit is encoded by two genes, CNA1 and CNA2, and a single regulatory subunit (CNB1) (Cyert, 2003).”
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    Premisecitation

    Calcineurin is a metalloenzyme with a binuclear metal center made of Fe3+ and Zn2+.

    “Calcineurin is a metalloenzyme with a binuclear metal center made of Fe3+and Zn2+ (Aramburu et al., 2001; Hemenway and Heitman, 1999).”
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    Premisecitation

    In mammalian cells, three genes encode the calcineurin catalytic subunit (CnAα, CnAβ, CnAγ) and two genes encode the regulatory subunit (CnB1, CnB2).

    “In mammalian cells, three genes encoding the calcineurin catalytic subunit (CnAα, CnAβ, and CnAγ) and two genes encoding the calcineurin regulatory subunit (CnB1 and CnB2) have been identified (Rusnak and Mertz, 2000)”
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    Premisecitation

    C. neoformans can survive at host temperature via calcineurin-mediated regulatory mechanisms and requires calcineurin for virulence.

    “The pathogenic basidiomycete C. neoformans can survive at host temperature via calcineurin-mediated regulatory mechanisms and requires calcineurin for virulence (Brown et al., 2007; Odom et al., 1997).”
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    Premisecitation

    Mutation of CNB1 in C. albicans caused hypersensitivity to fluconazole, revealing its role in mediating survival during membrane stress.

    “Though calcineurin is not an essential gene in C. albicans, mutation of CNB1 caused hypersensitivity to fluconazole, revealing its role in mediating survival during membrane stress (Cruz et al., 2002).”
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    Premisecitation

    Genetic or pharmacologic repression of Hsp90 in A. fumigatus increases susceptibility to caspofungin and abolishes the paradoxical effect of caspofungin.

    “Genetic or pharmacologic repression of Hsp90 resulted in various similar phenotypic consequences compared to calcineurin deletion, such as impaired hyphal elongation, decreased β-glucan content of the cell wall, defective sporulation, and increased susceptibility to caspofungin with abolition of the paradoxical effect of this drug”
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    Premisereasoning

    Hsp90 inhibition abrogates calcineurin dependent stress responses, changing fungistatic drugs to fungicidal agents.

    “Hsp90 inhibition abrogates calcineurin dependent stress responses, changing fungistatic drugs to fungicidal agents.”
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    Premisecitation

    Analyses of cell wall composition in the A. fumigatus ΔcnaA ΔcnaB strain showed that the cell wall was thicker in all calcineurin deletion mutants and displayed abnormal septa.

    “Analyses of the cell wall composition in the A. fumigatus ΔcnaA ΔcnaB strain (Juvvadi et al., 2011) showed that the cell wall was thicker in all the calcineurin deletion mutants and displayed abnormal septa.”
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    Premisecitation

    Transcriptional profiling revealed decreased fksA expression correlated with reduced β-1,3-glucan content in the A. fumigatus ΔcnaA strain but not in the ΔcrzA strain, indicating that CrzA may not have a significant role in regulation of β-1,3-glucan biosynthesis in A. fumigatus.

    “Transcriptional profiling of cell wall biosynthesis genes revealed decreased fksA expression, which correlated with reduced β-1,3-glucan content in the A. fumigatus ΔcnaA strain but not in the ΔcrzA strain, indicating that CrzA may not have a significant role in the regulation of β-1,3-glucan biosynthesis in A. fumigatus (Cramer et al., 2008).”
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    Premisecitation

    In B. cinerea, deletion of crz1 caused defects in cell wall and membrane integrity, resulting in slowed growth rate, conidiation and hyphal penetration of leaves, and impaired response to cationic stress.

    “In the necrotrophic fungus Botrytis cinerea, deletion of crz1 caused defects in cell wall and membrane integrity, resulting in slowed growth rate, conidiation and hyphal penetration of the leaves in addition to an impaired response to cationic stress (Schumacher et al., 2008).”
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    Premisecitation

    Calcineurin is not an essential gene in A. fumigatus, but it is a key phosphatase involved in regulating differentiation and fitness of this opportunistic pathogen.

    “Though calcineurin is not an essential gene in A. fumigatus, it is a key phosphatase involved in regulating the differentiation and fitness of this opportunistic pathogen (Ferreira et al., 2007; Steinbach et al., 2006).”
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    Premisecitation

    CaM is not required for septal localization of CnaA, but it is required for calcineurin function at the hyphal septum, and the PxIxIT substrate binding motif in CnaA is required for its localization at the hyphal septum.

    “While CaM, the key protein known to activate calcineurin, is not required for septal localization of CnaA, it is required for calcineurin function at the hyphal septum and the PxIxIT substrate binding motif in CnaA is required for its localization at the hyphal septum.”
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    Interpretationcitation

    In C. albicans, calcineurin is required specifically for cell survival during membrane stress but not cell wall stress.

    “In contrast, there was no difference in sensitivity of the cnb1 mutant compared to the wild type strain following treatment with nikkomycin Z, a chitin synthase inhibitor, or the β-1,3 glucan synthase inhibitor caspofungin, indicating that calcineurin in C. albicans is required specifically for cell survival during membrane stress but not cell wall stress (Cruz et al., 2002).”
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    Interpretationcitation

    Overall, CRZ1 deletion resulted in an only partial loss of tolerance to both fluconazole and micafungin compared to CNA1 deletion, supporting that crz1p contributes to this response but is not the only downstream effector.

    “Overall, CRZ1 deletion resulted in an only partial loss of tolerance to both fluconazole and micafungin compared to CNA1 deletion, which further supports that crz1p contributes to this response but is not the only downstream effector (Cowen et al., 2006; Singh et al., 2009).”
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    Premisecitation

    While calcineurin is required for virulence of A. fumigatus, the calcineurin complex (CnaA and CnaB) selectively localizes at hyphal tips and septa to direct proper hyphal growth and regular septum formation.

    “While calcineurin is required for virulence of A. fumigatus, the calcineurin complex (CnaA and CnaB) also selectively localizes at the hyphal tips and septa to direct proper hyphal growth and regular septum formation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Juvvadi et al., 2008

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    • cites Juvvadi et al., 2011 source

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    Premisecitation

    Ergosterol biosynthetic pathways and mechanisms of azole resistance are multiple and complex and may substantially differ between molds and yeasts.

    “The ergosterol biosynthetic pathways and mechanisms of azole resistance are multiple and complex, and may substantially differ between molds and yeasts (Ferreira et al., 2005).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ferreira et al., 2005

      Not checked in the free run.

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    Premisecitation

    In C. albicans, calcineurin inhibitors display no inherent antifungal effect but are synergistic with fluconazole in vitro and in vivo at concentrations achievable in humans.

    “In C. albicans, calcineurin inhibitors displayed no inherent antifungal effect, but were synergistic in combination with fluconazole in vitro and in vivo at concentrations achievable in humans (Maesaki et al., 1998; Marchetti et al., 2000a; Marchetti et al., 2000b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Maesaki et al., 1998

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    • cites Marchetti et al., 2000a

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    • cites Marchetti et al., 2000b

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    Premisecitation

    Calcineurin inhibitors are active in vitro against A. fumigatus as monotherapy and potentiate the effect of caspofungin.

    “However, these calcineurin inhibitors are active in vitro against A. fumigatus as monotherapy and potentiate the effect of caspofungin (High, 1994; Kontoyiannis et al., 2003; Steinbach et al., 2004a; Steinbach et al., 2004b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites High, 1994

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    • cites Kontoyiannis et al., 2003

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    • cites Steinbach et al., 2004a

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    Premisecitation

    Calcineurin A and B subunits localize at the septum and play a key role in septum formation and cell wall integrity.

    “These results suggest the possibility of Hsp90-calcineurin interactions under cell wall stress conditions, as both the calcineurin A and B subunits were shown to localize at the septum and to play a key role in septum formation and cell wall integrity (Juvvadi et al., 2011; Steinbach et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Juvvadi et al., 2011 source

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    • cites Steinbach et al., 2006 source

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    Premisecitation

    In murine invasive aspergillosis, CsA is associated with decreased median survival, while FK506 and sirolimus result in similar survival curves compared to the untreated group.

    “While CsA was associated with decreased median survival, FK506 and sirolimus resulted in similar survival curves compared to the untreated group.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites High and Washburn, 1997

      Not checked in the free run.

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    Premisecitation

    Retrospective clinical analyses suggest a lower incidence of invasive aspergillosis and lower mortality rates among patients treated with FK506 compared to those receiving CsA.

    “Some retrospective clinical analyses also suggested a lower incidence of invasive aspergillosis with lower mortality rates among patients treated with FK506 compared to those receiving CsA (Singh et al., 2003; Torre-Cisneros et al., 1991).”
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    • cites Singh et al., 2003

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    Premisecitation

    In A. fumigatus, the ΔcrzA strain exhibits sporulation and cell wall defects.

    “Akin to the Hsp90 repression strain, the A. fumigatus ΔcrzA strain exhibited the same sporulation and cell wall defects, and was also hypersensitive to caspofungin and incapable of generating a paradoxical response at high caspofungin concentrations (Cramer et al., 2008; Fortwendel et al., 2010; Fortwendel et al., 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
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    Premisecitation

    In A. fumigatus, Hsp90 is abundantly distributed in the cytosol under standard growth conditions, moves to the nucleus under heat stress, and moves to the cell wall, septa, and hyphal tips in response to caspofungin-induced cell wall stress.

    “Subcellular localization analysis of A. fumigatus Hsp90 using an EGFP-tagged strain showed that Hsp90 was abundantly distributed within the cytosol under standard growth conditions and moved to the nucleus under heat stress or to the cell wall, septa and hyphal tips in response to the cell wall stress induced by caspofungin (Lamoth et al., 2012).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lamoth et al., 2012 source

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48 of 48

  • The paper relies on this without support.

    The current antifungal armamentarium is limited.

    “coupled with the current limited armamentarium of antifungals”

  • The paper relies on this without support.

    The calcineurin pathway is as yet incompletely explored.

    “the as yet incompletely explored calcineurin pathway”
2 of 2

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Authors
Juvvadi, P. R., Lamoth, F., & Steinbach, W. J.
Affiliations
Duke University (US)
Corresponding author
Juvvadi, Praveen R.
ORCID
Venue
Fungal Biology Reviews
Publisher
Elsevier BV
Published
2014-10
Volume
28
Issue
2-3
Pages
56-69
ISSN
1749-4613 (ISSN-L)
DOI
10.1016/j.fbr.2014.02.004
PMC
PMC4219591
OpenAlex
W2000200558
Semantic Scholar
0ee482d9ef242eb9c456f934be38afd2f9257f6e
Cited by
116
References
138
Citations by year
2026: 5 · 2025: 5 · 2024: 6 · 2023: 11 · 2022: 17 · 2021: 9 · 2020: 20 · 2019: 9 · 2018: 7 · 2017: 7 · 2016: 12 · 2015: 8
FWCI
3.69
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Fungal Biology Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
  • NIH/NIAID (R56 AI077648-01A2, R21 AI097541-01A1)
  • Swiss Foundation for Medical-Biological Grants
  • Swiss National Science Foundation (PASMP3-142746)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
  • Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
calcineurin signaling, fungal stress response, hyphal growth, drug resistance, fungal pathogenesis, calcineurin inhibitors, FK506, cyclosporine, antifungal drug development, yeast morphogenesis, invasive fungal pathogen, virulence

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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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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