The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth

Eng, Wai-Kwong; Faucette, Leo F.; McLaughlin, Megan M.; Cafferkey, Robert; Koltin, Y.; Morris, Rene A.; Young, Peter R.; Johnson, Randall K.; Livi, George P.

doi:10.1016/0378-1119(94)90633-5

Cited by 83 publications

(59 citation statements)

References 45 publications

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“…The fungal 1,3-β-glucan synthase complex consists of at least two components, a membranebound catalytic subunit and a detergent-soluble GTP-binding regulatory subunit. In S. cerevisiae, a gene which codes for a 215-kDa integral membrane protein was first isolated as FKS1 (Douglas et al, 1994;Eng et al, 1994), and several different fks1 alleles which cause altered sensitivities to cell wall inhibitors were also identified (Ram et al, 1995;Castro et al, 1995). The independently isolated genes were proven to code for the catalytic subunit of 1,3-β-glucan synthase using product entrapment, and are also named GSC1 (Inoue et al, 1995).…”

Section: Genes Involved In Cell Wall Integritymentioning

confidence: 99%

Genetic control of fission yeast cell wall synthesis: the genes involved in wall biogenesis and their interactions in Schizosaccharomyces pombe.

Ishiguro

1998

Genes Genet. Syst.

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Section: Genes Involved In Cell Wall Integritymentioning

confidence: 99%

Genetic control of fission yeast cell wall synthesis: the genes involved in wall biogenesis and their interactions in Schizosaccharomyces pombe.

Ishiguro

1998

Genes Genet. Syst.

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“…For example, mutations that disrupt calcineurin function are lethal in combination with several mutations that impair cell wall synthesis, including fks1⌬ (11)(12)(13). FKS1 and FKS2 are a pair of homologous genes responsible for the synthesis of ␤1,3-glucan (11,12,14), which is a glucose homopolymer. Since ␤1,3-glucan is an essential cell wall component, yeast cells require both the FKS1 and FKS2 genes for viability.…”

mentioning

confidence: 99%

“…In a fks1⌬ mutant, the transcription of FKS2 gene is up-regulated to compensate for the loss of FKS1 function (14). Because calcineurin is required for the activation of FKS2 transcription, strains lacking both FKS1 and calcineurin functions are inviable due to the lack of FKS2 expression (11)(12)(13). Recently, it has been shown that the calcineurin-dependent FKS2 transcriptional regulation is mediated by a zinc finger containing transcription factor CRZ1/ TCN1, which associates with a DNA element (calcineurin-dependent responsive element (CDRE)) located in the promoter of the FKS2 gene (15).…”

mentioning

confidence: 99%

Identification of a Novel Region Critical for Calcineurin Function in Vivo and in Vitro

Jiang

Cyert

1999

Journal of Biological Chemistry

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Calcineurin is a Ca2؉ /calmodulin-regulated protein phosphatase that plays critical functional roles in T-cell activation and other Ca 2؉ -mediated signal transduction pathways in mammalian cells. In Saccharomyces cerevisiae, calcineurin regulates the transcription of several genes involved in maintaining ion homeostasis (PMC1, PMR1, and PMR2) and cell wall synthesis (FKS2). In this paper, we report the identification and characterization of 11 single amino acid substitutions in the yeast calcineurin catalytic subunit Cna1p. We show that six substitutions (R177G, F211S, S232F, D258V, L259P, and A262P) affect the stability of calcineurin and that two substitutions (V385D and M400R) disrupt the interaction between Cna1p and the calcineurin regulatory subunit Cnb1p. We also identify three mutations (S373P, H375L, and L379S) that are clustered between the catalytic and the calcineurin B subunit-binding domains. These mutations do not significantly affect the ability of Cna1p to interact with Cnb1p, calmodulin, or Fkb1p (FK506-binding protein). However, these residue substitutions dramatically affect calcineurin activity both in vitro and in vivo. Thus, by using a random mutagenesis approach, we have shown for the first time that the linker region of the calcineurin catalytic subunit, as defined by the Ser 373 , His 375 , and Leu 379 residues, is crucial for its function as a phosphatase.Calcineurin, also known as PP2B, is a Ser/Thr-specific protein phosphatase (1). Calcineurin is tightly regulated by Ca 2ϩ / calmodulin, and it plays critical functional roles in many calcium-mediated signal transduction pathways. For example, calcineurin is required during T-cell activation for the transcriptional regulation of interleukin 2 (IL2) and other cytokine genes (2, 3). In human T-cells, calcineurin directly binds to and dephosphorylates the transcription factor NFAT.1 The dephosphorylated NFAT then translocates from the cytosol to the nucleus and activates the transcription of IL2 and other cytokine genes required for T-cell activation and proliferation (4, 5). The immunosuppressive drugs FK506 and cyclosporin A, in association with their respective cellular receptor proteins FKBP12 and cyclophilin A, bind to calcineurin and inhibit its phosphatase activity (6), thus preventing the calcineurin-dependent transcriptional activation of cytokine genes and T-cell activation (7).In the budding yeast Saccharomyces cerevisiae, calcineurindeficient strains exhibit normal growth under standard conditions (8 -10). However, calcineurin function is required for cell viability under some specific growth conditions. For example, mutations that disrupt calcineurin function are lethal in combination with several mutations that impair cell wall synthesis, including fks1⌬ (11-13). FKS1 and FKS2 are a pair of homologous genes responsible for the synthesis of ␤1, 3-glucan (11, 12, 14), which is a glucose homopolymer. Since ␤1,3-glucan is an essential cell wall component, yeast cells require both the FKS1 and FKS2 genes for viability. In a fks...

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“…The echinocandin-resistance level conferred by hot-spot mutations in FKS1 or FKS2 may also depend on the relative expression of these genes, which can vary more than 20-fold (Garcia-Effron et al 2009a; Katiyar et al 2012). FKS2 expression is calcineurin dependent and down-regulated by FK506 (tacrolimus) (Eng et al 1994). Resistance conferred by FKS2 but not FKS1 is reversed following treatment with the calcineurin inhibitor FK506 .…”

Section: Fks Mechanism Of Resistancementioning

confidence: 99%

Mechanisms of Antifungal Drug Resistance

Cowen

Sanglard

Howard

et al. 2014

Cold Spring Harb Perspect Med

478

399

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Antifungal therapy is a central component of patient management for acute and chronic mycoses. Yet, treatment choices are restricted because of the sparse number of antifungal drug classes. Clinical management of fungal diseases is further compromised by the emergence of antifungal drug resistance, which eliminates available drug classes as treatment options. Once considered a rare occurrence, antifungal drug resistance is on the rise in many high-risk medical centers. Most concerning is the evolution of multidrug-resistant organisms refractory to several different classes of antifungal agents, especially among common Candida species. The mechanisms responsible are mostly shared by both resistant strains displaying inherently reduced susceptibility and those acquiring resistance during therapy. The molecular mechanisms include altered drug affinity and target abundance, reduced intracellular drug levels caused by efflux pumps, and formation of biofilms. New insights into genetic factors regulating these mechanisms, as well as cellular factors important for stress adaptation, provide a foundation to better understand the emergence of antifungal drug resistance.

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The yeast FKS1 gene encodes a novel membrane protein, mutations in which confer FK506 and cyclosporin A hypersensitivity and calcineurin-dependent growth

Cited by 83 publications

References 45 publications

Genetic control of fission yeast cell wall synthesis: the genes involved in wall biogenesis and their interactions in Schizosaccharomyces pombe.

Genetic control of fission yeast cell wall synthesis: the genes involved in wall biogenesis and their interactions in Schizosaccharomyces pombe.

Identification of a Novel Region Critical for Calcineurin Function in Vivo and in Vitro

Mechanisms of Antifungal Drug Resistance

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