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Calcineurin is essential for survival during membrane stress in Candida albicans.

Publication ,  Journal Article
Cruz, MC; Goldstein, AL; Blankenship, JR; Del Poeta, M; Davis, D; Cardenas, ME; Perfect, JR; McCusker, JH; Heitman, J
Published in: EMBO J
February 15, 2002

The immunosuppressants cyclosporin A (CsA) and FK506 inhibit the protein phosphatase calcineurin and block T-cell activation and transplant rejection. Calcineurin is conserved in microorganisms and plays a general role in stress survival. CsA and FK506 are toxic to several fungi, but the common human fungal pathogen Candida albicans is resistant. However, combination of either CsA or FK506 with the antifungal drug fluconazole that perturbs synthesis of the membrane lipid ergosterol results in potent, synergistic fungicidal activity. Here we show that the C.albicans FK506 binding protein FKBP12 homolog is required for FK506 synergistic action with fluconazole. A mutation in the calcineurin B regulatory subunit that confers dominant FK506 resistance (CNB1-1/CNB1) abolished FK506-fluconazole synergism. Candida albicans mutants lacking calcineurin B (cnb1/cnb1) were found to be viable and markedly hypersensitive to fluconazole or membrane perturbation with SDS. FK506 was synergistic with fluconazole against azole-resistant C.albicans mutants, against other Candida species, or when combined with different azoles. We propose that calcineurin is part of a membrane stress survival pathway that could be targeted for therapy.

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Published In

EMBO J

DOI

ISSN

0261-4189

Publication Date

February 15, 2002

Volume

21

Issue

4

Start / End Page

546 / 559

Location

England

Related Subject Headings

  • Tacrolimus
  • Methyltransferases
  • Genes, Fungal
  • Gene Expression Regulation, Fungal
  • Fluconazole
  • Drug Resistance, Microbial
  • Developmental Biology
  • DNA Primers
  • Cyclosporine
  • Candida albicans
 

Citation

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Cruz, M. C., Goldstein, A. L., Blankenship, J. R., Del Poeta, M., Davis, D., Cardenas, M. E., … Heitman, J. (2002). Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J, 21(4), 546–559. https://doi.org/10.1093/emboj/21.4.546
Cruz, M Cristina, Alan L. Goldstein, Jill R. Blankenship, Maurizio Del Poeta, Dana Davis, Maria E. Cardenas, John R. Perfect, John H. McCusker, and Joseph Heitman. “Calcineurin is essential for survival during membrane stress in Candida albicans.EMBO J 21, no. 4 (February 15, 2002): 546–59. https://doi.org/10.1093/emboj/21.4.546.
Cruz MC, Goldstein AL, Blankenship JR, Del Poeta M, Davis D, Cardenas ME, et al. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J. 2002 Feb 15;21(4):546–59.
Cruz, M. Cristina, et al. “Calcineurin is essential for survival during membrane stress in Candida albicans.EMBO J, vol. 21, no. 4, Feb. 2002, pp. 546–59. Pubmed, doi:10.1093/emboj/21.4.546.
Cruz MC, Goldstein AL, Blankenship JR, Del Poeta M, Davis D, Cardenas ME, Perfect JR, McCusker JH, Heitman J. Calcineurin is essential for survival during membrane stress in Candida albicans. EMBO J. 2002 Feb 15;21(4):546–559.

Published In

EMBO J

DOI

ISSN

0261-4189

Publication Date

February 15, 2002

Volume

21

Issue

4

Start / End Page

546 / 559

Location

England

Related Subject Headings

  • Tacrolimus
  • Methyltransferases
  • Genes, Fungal
  • Gene Expression Regulation, Fungal
  • Fluconazole
  • Drug Resistance, Microbial
  • Developmental Biology
  • DNA Primers
  • Cyclosporine
  • Candida albicans