Home LiteratureArticle Details
PMID: 16113294 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Calcineurin is required for Candida albicans to survive calcium stress in serum.

Infection and immunity ·Vol. 73 ·No. 9 ·2005-09-00 ·Pages 5767-74

Blankenship JR, Heitman J

Abstract

The calcium-activated protein phosphatase calcineurin plays a critical role in the virulence of Candida albicans. Previous studies demonstrated that calcineurin is not required for the yeast-hypha dimorphic transition, host cell adherence, or host cell injury, which are all established virulence attributes of this organism. Calcineurin is, however, essential for survival in serum and disseminated infection. Here we identify the component of serum that is toxic to calcineurin mutant cells. Proteins, peptides, lipids, and other hydrophobic components were all excluded as essential toxic elements. Upon testing of small molecules present in serum, we discovered that calcineurin protects cells from stress caused by the endogenous levels of calcium ions present in serum. These studies illustrate how calcineurin functions in a calcium homeostatic pathway that enables a common human commensal to survive passage through the hostile environment of the bloodstream to establish deep-seated infections and cause disease.

MeSH Terms
Animals Calcineurin/physiology Calcineurin Inhibitors Calcium/metabolism Candida albicans/growth & development,pathogenicity,physiology Cattle Iron/physiology Serum/microbiology Trans-Activators/physiology Zinc/physiology
Chemicals
Calcineurin Inhibitors Trans-Activators Iron Calcineurin Zinc Calcium
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Blankenship Jill R
Department of Molecular Genetics and Microbiology, 322 CARL Building, Box 3546, Duke University Medical Center, Research Drive, Durham, NC 27710, USA.
Heitman Joseph
References (45)
45 references, click to expand
  1. Teaching old drugs new tricks: reincarnating immunosuppressants as antifungal drugs.
    Curr Opin Investig Drugs. 2003 Feb;4(2):192-9 PMID: 12669381
  2. Management of seborrheic dermatitis and pityriasis versicolor.
    Am J Clin Dermatol. 2000 Mar-Apr;1(2):75-80 PMID: 11702314
  3. Calcineurin is essential for Candida albicans survival in serum and virulence.
    Eukaryot Cell. 2003 Jun;2(3):422-30 PMID: 12796287
  4. Calcineurin is essential for virulence in Candida albicans.
    Infect Immun. 2003 Sep;71(9):5344-54 PMID: 12933882
  5. Molecular genetics of fungal siderophore biosynthesis and uptake: the role of siderophores in iron uptake and storage.
    Appl Microbiol Biotechnol. 2003 Sep;62(4):316-30 PMID: 12759789
  6. Calcineurin signaling in Saccharomyces cerevisiae: how yeast go crazy in response to stress.
    Biochem Biophys Res Commun. 2003 Nov 28;311(4):1143-50 PMID: 14623300
  7. Candida infections of medical devices.
    Clin Microbiol Rev. 2004 Apr;17(2):255-67 PMID: 15084500
  8. Hph1p and Hph2p, novel components of calcineurin-mediated stress responses in Saccharomyces cerevisiae.
    Eukaryot Cell. 2004 Jun;3(3):695-704 PMID: 15189990
  9. Identification of the dialysable serum inducer of germ-tube formation in Candida albicans.
    Microbiology. 2004 Sep;150(Pt 9):3041-9 PMID: 15347762
  10. Regulation of Candida albicans morphogenesis by fatty acid metabolites.
    Infect Immun. 2004 Nov;72(11):6206-10 PMID: 15501745
  11. Human serum interactions with Candida albicans.
    J Immunol. 1968 Jul;101(1):128-32 PMID: 4173934
  12. Anti-Candida factors in serum and their inhibitors. II. Identification of a Candida-clumping factor and the influence of the immune response on the morphology of Candida and on anti-Candida activity of serum in rabbits.
    J Infect Dis. 1972 Feb;125(2):115-22 PMID: 4550226
  13. Factors present in serum and seminal plasma which promote germ-tube formation and mycelial growth of Candida albicans.
    J Gen Microbiol. 1974 Jun;82(2):261-72 PMID: 4608853
  14. Clearance of Candida albicans from the bloodstream of rabbits.
    Infect Immun. 1974 Dec;10(6):1420-5 PMID: 4611929
  15. Experimental Candida albicans infection in conventional mice and germfree rats.
    Infect Immun. 1976 Jul;14(1):33-8 PMID: 780278
  16. Isolation of the Candida albicans gene for orotidine-5'-phosphate decarboxylase by complementation of S. cerevisiae ura3 and E. coli pyrF mutations.
    Mol Gen Genet. 1984;198(2):179-82 PMID: 6394964
  17. Getting started with yeast.
    Methods Enzymol. 1991;194:3-21 PMID: 2005794
  18. Protein phosphatase type 2B (calcineurin)-mediated, FK506-sensitive regulation of intracellular ions in yeast is an important determinant for adaptation to high salt stress conditions.
    EMBO J. 1993 Nov;12(11):4063-71 PMID: 7693452
  19. Calcineurin-dependent growth control in Saccharomyces cerevisiae mutants lacking PMC1, a homolog of plasma membrane Ca2+ ATPases.
    J Cell Biol. 1994 Feb;124(3):351-63 PMID: 7507493
  20. Calcium regulation of calcineurin phosphatase activity by its B subunit and calmodulin. Role of the autoinhibitory domain.
    J Biol Chem. 1995 Jan 6;270(1):340-6 PMID: 7814394
  21. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex.
    Cell. 1995 Aug 11;82(3):507-22 PMID: 7543369
  22. Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex.
    Nature. 1995 Dec 7;378(6557):641-4 PMID: 8524402
  23. Calcineurin is required for virulence of Cryptococcus neoformans.
    EMBO J. 1997 May 15;16(10):2576-89 PMID: 9184205
  24. Calcineurin acts through the CRZ1/TCN1-encoded transcription factor to regulate gene expression in yeast.
    Genes Dev. 1997 Dec 15;11(24):3432-44 PMID: 9407035
  25. Tcn1p/Crz1p, a calcineurin-dependent transcription factor that differentially regulates gene expression in Saccharomyces cerevisiae.
    Genes Dev. 1997 Dec 15;11(24):3445-58 PMID: 9407036
  26. Iron and oxidative stress in bacteria.
    Arch Biochem Biophys. 2000 Jan 1;373(1):1-6 PMID: 10620317
  27. Comparison of the roles of calcineurin in physiology and virulence in serotype D and serotype A strains of Cryptococcus neoformans.
    Infect Immun. 2000 Feb;68(2):982-5 PMID: 10639477
  28. Calcineurin: from structure to function.
    Curr Top Cell Regul. 2000;36:237-95 PMID: 10842755
  29. Free radicals and antioxidants in the year 2000. A historical look to the future.
    Ann N Y Acad Sci. 2000;899:136-47 PMID: 10863535
  30. Depletion of the squalene synthase (ERG9) gene does not impair growth of Candida glabrata in mice.
    Antimicrob Agents Chemother. 2000 Sep;44(9):2411-8 PMID: 10952588
  31. Candida albicans RIM101 pH response pathway is required for host-pathogen interactions.
    Infect Immun. 2000 Oct;68(10):5953-9 PMID: 10992507
  32. Calcineurin: form and function.
    Physiol Rev. 2000 Oct;80(4):1483-521 PMID: 11015619
  33. Fluconazole plus cyclosporine: a fungicidal combination effective against experimental endocarditis due to Candida albicans.
    Antimicrob Agents Chemother. 2000 Nov;44(11):2932-8 PMID: 11036003
  34. Calcineurin is essential for survival during membrane stress in Candida albicans.
    EMBO J. 2002 Feb 15;21(4):546-59 PMID: 11847103
  35. Crystal structure of calcineurin-cyclophilin-cyclosporin shows common but distinct recognition of immunophilin-drug complexes.
    Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12037-42 PMID: 12218175
  36. Crystal structure of human calcineurin complexed with cyclosporin A and human cyclophilin.
    Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13522-6 PMID: 12357034
  37. Ergosterol biosynthesis inhibitors become fungicidal when combined with calcineurin inhibitors against Candida albicans, Candida glabrata, and Candida krusei.
    Antimicrob Agents Chemother. 2003 Mar;47(3):956-64 PMID: 12604527
  38. Regulation of the calmodulin-stimulated protein phosphatase, calcineurin.
    J Biol Chem. 1998 May 29;273(22):13367-70 PMID: 9593662
  39. Synergic effects of tactolimus and azole antifungal agents against azole-resistant Candida albican strains.
    J Antimicrob Chemother. 1998 Dec;42(6):747-53 PMID: 10052898
  40. Calcineurin. Structure, function, and inhibition.
    Cell Biochem Biophys. 1999;30(1):115-51 PMID: 10099825
  41. Ras signaling is required for serum-induced hyphal differentiation in Candida albicans.
    J Bacteriol. 1999 Oct;181(20):6339-46 PMID: 10515923
  42. A SUBSTANCE IN BLOOD LETHAL FOR CANDIDA ALBICANS.
    Nature. 1964 Jan 18;201:309 PMID: 14110469
  43. The calcineurin target, Crz1, functions in azole tolerance but is not required for virulence of Candida albicans.
    Infect Immun. 2004 Dec;72(12):7330-3 PMID: 15557662
  44. Transcriptional profiling in Candida albicans reveals new adaptive responses to extracellular pH and functions for Rim101p.
    Mol Microbiol. 2004 Dec;54(5):1335-51 PMID: 15554973
  45. Calcineurin A of Candida albicans: involvement in antifungal tolerance, cell morphogenesis and virulence.
    Mol Microbiol. 2003 May;48(4):959-76 PMID: 12753189
Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
0019-9567
DOI
10.1128/IAI.73.9.5767-5774.2005
Published
2005-09-00
Pages
5767-74
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC1231066
Subset
IM
Grants
NIAID NIH HHS · P01 AI044975 · United States
NIAID NIH HHS · R01 AI050438 · United States
NIAID NIH HHS · AI-44975 · United States
NIAID NIH HHS · AI-50438 · United States
External Links
PubMed source DOI: 10.1128/IAI.73.9.5767-5774.2005 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2