Home LiteratureArticle Details
PMID: 12006487 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Essential role of calcineurin in response to endoplasmic reticulum stress.

The EMBO journal ·Vol. 21 ·No. 10 ·2002-05-15 ·Pages 2343-53

Bonilla M, Nastase KK, Cunningham KW

Abstract

Depletion of calcium ions (Ca2+) from the endoplasmic reticulum (ER) of yeast cells resulted in the activation of the unfolded protein response (UPR) signaling pathway involving Ire1p and Hac1p. The depleted ER also stimulated Ca2+ influx at the plasma membrane through the Cch1p-Mid1p Ca2+ channel and another system. Surprisingly, both Ca2+ influx systems were stimulated upon accumulation of misfolded proteins in the ER even in the presence of Ca2+. The ability of misfolded ER proteins to stimulate Ca2+ influx at the plasma membrane did not require Ire1p or Hac1p, and Ca2+ influx and signaling factors were not required for initial UPR signaling. However, activation of the Ca2+ channel, calmodulin, calcineurin and other factors was necessary for long-term survival of cells undergoing ER stress. A similar calcium cell survival (CCS) pathway operates in the pathogenic fungi and promotes resistance to azole antifungal drugs. These findings reveal an unanticipated new regulatory mechanism that couples ER stress to Ca2+ influx and signaling pathways, which help to prevent cell death and promote resistance to an important class of fungistatic drugs.

MeSH Terms
Antifungal Agents/pharmacology Blotting, Northern Calcineurin/physiology Calcium Channels/physiology Calcium Signaling/physiology Calmodulin/physiology Cell Membrane/physiology Cell Survival/physiology DNA, Fungal/genetics Endoplasmic Reticulum/physiology Genotype Polymerase Chain Reaction Protein Folding Saccharomyces cerevisiae/drug effects,genetics,physiology Signal Transduction/physiology Stress, Mechanical Tunicamycin/pharmacology
Chemicals
Antifungal Agents Calcium Channels Calmodulin DNA, Fungal Tunicamycin Calcineurin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Bonilla Myriam
Department of Biology, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, USA.
Nastase Kristin K
Cunningham Kyle W
References (70)
70 references, click to expand
  1. Steady-state free Ca(2+) in the yeast endoplasmic reticulum reaches only 10 microM and is mainly controlled by the secretory pathway pump pmr1.
    EMBO J. 1999 Sep 1;18(17):4733-43 PMID: 10469652
  2. 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
  3. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway.
    Science. 1996 Sep 20;273(5282):1725-8 PMID: 8781238
  4. Calcium pools, calcium entry, and cell growth.
    Biosci Rep. 1996 Apr;16(2):139-57 PMID: 8790919
  5. Signalling from endoplasmic reticulum to nucleus: transcription factor with a basic-leucine zipper motif is required for the unfolded protein-response pathway.
    Genes Cells. 1996 Sep;1(9):803-17 PMID: 9077435
  6. Deregulation of the first N-glycosylation gene, ALG7, perturbs the expression of G1 cyclins and cell cycle arrest in Saccharomyces cerevisiae.
    Biochem Biophys Res Commun. 1997 Aug 28;237(3):562-5 PMID: 9299404
  7. The yeast secretory pathway is perturbed by mutations in PMR1, a member of a Ca2+ ATPase family.
    Cell. 1989 Jul 14;58(1):133-45 PMID: 2526682
  8. A hyper-recombination mutation in S. cerevisiae identifies a novel eukaryotic topoisomerase.
    Cell. 1989 Jul 28;58(2):409-19 PMID: 2546682
  9. cDNA cloning, functional expression, and mRNA tissue distribution of a third organellar Ca2+ pump.
    J Biol Chem. 1989 Nov 5;264(31):18561-8 PMID: 2553713
  10. Loss of BiP/GRP78 function blocks translocation of secretory proteins in yeast.
    J Cell Biol. 1990 Jun;110(6):1885-95 PMID: 2190988
  11. Multiple Ca2+/calmodulin-dependent protein kinase genes in a unicellular eukaryote.
    EMBO J. 1991 Jun;10(6):1511-22 PMID: 2026147
  12. Capacitative calcium entry revisited.
    Cell Calcium. 1990 Nov-Dec;11(10):611-24 PMID: 1965707
  13. Can calmodulin function without binding calcium?
    Cell. 1991 Jun 14;65(6):949-59 PMID: 2044154
  14. Sec61p and BiP directly facilitate polypeptide translocation into the ER.
    Cell. 1992 Apr 17;69(2):353-65 PMID: 1568250
  15. Regulatory subunit (CNB1 gene product) of yeast Ca2+/calmodulin-dependent phosphoprotein phosphatases is required for adaptation to pheromone.
    Mol Cell Biol. 1992 Aug;12(8):3460-9 PMID: 1321337
  16. The yeast Ca(2+)-ATPase homologue, PMR1, is required for normal Golgi function and localizes in a novel Golgi-like distribution.
    Mol Biol Cell. 1992 Jun;3(6):633-54 PMID: 1379856
  17. Brefeldin A, thapsigargin, and AIF4- stimulate the accumulation of GRP78 mRNA in a cycloheximide dependent manner, whilst induction by hypoxia is independent of protein synthesis.
    J Cell Physiol. 1992 Sep;152(3):545-52 PMID: 1506413
  18. Isogenic strain construction and gene mapping in Candida albicans.
    Genetics. 1993 Jul;134(3):717-28 PMID: 8349105
  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. Genetic interactions between KAR2 and SEC63, encoding eukaryotic homologues of DnaK and DnaJ in the endoplasmic reticulum.
    Mol Biol Cell. 1993 Nov;4(11):1145-59 PMID: 8305736
  21. MID1, a novel Saccharomyces cerevisiae gene encoding a plasma membrane protein, is required for Ca2+ influx and mating.
    Mol Cell Biol. 1994 Dec;14(12):8259-71 PMID: 7526155
  22. Saccharomyces cerevisiae CNE1 encodes an endoplasmic reticulum (ER) membrane protein with sequence similarity to calnexin and calreticulin and functions as a constituent of the ER quality control apparatus.
    J Biol Chem. 1995 Jan 6;270(1):244-53 PMID: 7814381
  23. Differential expression and function of two homologous subunits of yeast 1,3-beta-D-glucan synthase.
    Mol Cell Biol. 1995 Oct;15(10):5671-81 PMID: 7565718
  24. Manganese effectively supports yeast cell-cycle progression in place of calcium.
    J Cell Biol. 1995 Nov;131(4):1025-37 PMID: 7490280
  25. Calcineurin inhibits VCX1-dependent H+/Ca2+ exchange and induces Ca2+ ATPases in Saccharomyces cerevisiae.
    Mol Cell Biol. 1996 May;16(5):2226-37 PMID: 8628289
  26. Structural organization, ion transport, and energy transduction of P-type ATPases.
    Biochim Biophys Acta. 1996 May 6;1286(1):1-51 PMID: 8634322
  27. Activation of NF-kappa B by ER stress requires both Ca2+ and reactive oxygen intermediates as messengers.
    FEBS Lett. 1996 Aug 26;392(2):129-36 PMID: 8772190
  28. Elevated cytosolic free Ca2+ concentrations and massive Ca2+ accumulation within vacuoles, in yeast mutant lacking PMR1, a homolog of Ca2+ -ATPase.
    FEBS Lett. 1996 Aug 26;392(2):194-200 PMID: 8772202
  29. Temperature-induced expression of yeast FKS2 is under the dual control of protein kinase C and calcineurin.
    Mol Cell Biol. 1998 Feb;18(2):1013-22 PMID: 9447998
  30. The endoplasmic reticulum Ca2+ store: a view from the lumen.
    Trends Biochem Sci. 1998 Jan;23(1):10-4 PMID: 9478128
  31. Designer deletion strains derived from Saccharomyces cerevisiae S288C: a useful set of strains and plasmids for PCR-mediated gene disruption and other applications.
    Yeast. 1998 Jan 30;14(2):115-32 PMID: 9483801
  32. Yeast putative transcription factors involved in salt tolerance.
    FEBS Lett. 1998 Mar 27;425(2):323-8 PMID: 9559673
  33. The medial-Golgi ion pump Pmr1 supplies the yeast secretory pathway with Ca2+ and Mn2+ required for glycosylation, sorting, and endoplasmic reticulum-associated protein degradation.
    Mol Biol Cell. 1998 May;9(5):1149-62 PMID: 9571246
  34. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells.
    Genes Dev. 1998 Jun 15;12(12):1812-24 PMID: 9637683
  35. The ERO1 gene of yeast is required for oxidation of protein dithiols in the endoplasmic reticulum.
    Mol Cell. 1998 Jan;1(2):161-70 PMID: 9659913
  36. Ero1p: a novel and ubiquitous protein with an essential role in oxidative protein folding in the endoplasmic reticulum.
    Mol Cell. 1998 Jan;1(2):171-82 PMID: 9659914
  37. Cloning of mammalian Ire1 reveals diversity in the ER stress responses.
    EMBO J. 1998 Oct 1;17(19):5708-17 PMID: 9755171
  38. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control.
    Mol Cell Biol. 1998 Dec;18(12):7499-509 PMID: 9819435
  39. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.
    Nature. 1999 Jan 21;397(6716):271-4 PMID: 9930704
  40. Rabbit sarcoplasmic reticulum Ca(2+)-ATPase replaces yeast PMC1 and PMR1 Ca(2+)-ATPases for cell viability and calcineurin-dependent regulation of calcium tolerance.
    Mol Microbiol. 1999 Jan;31(2):545-56 PMID: 10027971
  41. Efficient homologous and illegitimate recombination in the opportunistic yeast pathogen Candida glabrata.
    Genetics. 1999 Mar;151(3):979-87 PMID: 10049916
  42. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response.
    Cell. 1997 Sep 19;90(6):1031-9 PMID: 9323131
  43. A homolog of mammalian, voltage-gated calcium channels mediates yeast pheromone-stimulated Ca2+ uptake and exacerbates the cdc1(Ts) growth defect.
    Mol Cell Biol. 1997 Nov;17(11):6339-47 PMID: 9343395
  44. The mechanism of Ca2+ transport by sarco(endo)plasmic reticulum Ca2+-ATPases.
    J Biol Chem. 1997 Nov 14;272(46):28815-8 PMID: 9360942
  45. 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
  46. The Saccharomyces cerevisiae CCH1 gene is involved in calcium influx and mating.
    FEBS Lett. 1997 Dec 15;419(2-3):259-62 PMID: 9428646
  47. Capacitative Ca2+ entry is closely linked to the filling state of internal Ca2+ stores: a study using simultaneous measurements of ICRAC and intraluminal [Ca2+].
    J Cell Biol. 1998 Jan 26;140(2):325-34 PMID: 9442108
  48. Synergistic antifungal activities of bafilomycin A(1), fluconazole, and the pneumocandin MK-0991/caspofungin acetate (L-743,873) with calcineurin inhibitors FK506 and L-685,818 against Cryptococcus neoformans.
    Antimicrob Agents Chemother. 2000 Mar;44(3):739-46 PMID: 10681348
  49. yam8(+), a Schizosaccharomyces pombe gene, is a potential homologue of the Saccharomyces cerevisiae MID1 gene encoding a stretch-activated Ca(2+)-permeable channel.
    Biochem Biophys Res Commun. 2000 Mar 5;269(1):265-9 PMID: 10694511
  50. Regulation of HMG-CoA reductase degradation requires the P-type ATPase Cod1p/Spf1p.
    J Cell Biol. 2000 Mar 6;148(5):915-24 PMID: 10704442
  51. Potent synergism of the combination of fluconazole and cyclosporine in Candida albicans.
    Antimicrob Agents Chemother. 2000 Sep;44(9):2373-81 PMID: 10952582
  52. A homolog of voltage-gated Ca(2+) channels stimulated by depletion of secretory Ca(2+) in yeast.
    Mol Cell Biol. 2000 Sep;20(18):6686-94 PMID: 10958666
  53. Schizosaccharomyces pombe ehs1p is involved in maintaining cell wall integrity and in calcium uptake.
    Mol Gen Genet. 2000 Sep;264(1-2):173-83 PMID: 11016847
  54. Presenilin-mediated modulation of capacitative calcium entry.
    Neuron. 2000 Sep;27(3):561-72 PMID: 11055438
  55. GSK-3 kinase Mck1 and calcineurin coordinately mediate Hsl1 down-regulation by Ca2+ in budding yeast.
    EMBO J. 2001 Mar 1;20(5):1074-85 PMID: 11230131
  56. Endoplasmic reticulum dysfunction--a common denominator for cell injury in acute and degenerative diseases of the brain?
    J Neurochem. 2001 Nov;79(4):719-25 PMID: 11723164
  57. Differential regulation of two Ca(2+) influx systems by pheromone signaling in Saccharomyces cerevisiae.
    Genetics. 2001 Dec;159(4):1527-38 PMID: 11779794
  58. Calcineurin is essential for survival during membrane stress in Candida albicans.
    EMBO J. 2002 Feb 15;21(4):546-59 PMID: 11847103
  59. Tunicamycin inhibition of polyisoprenyl N-acetylglucosaminyl pyrophosphate formation in calf-liver microsomes.
    Biochem Biophys Res Commun. 1975 Jul 8;65(1):248-57 PMID: 167767
  60. The specific site of tunicamycin inhibition in the formation of dolichol-bound N-acetylglucosamine derivatives.
    FEBS Lett. 1976 Nov 15;72(1):167-70 PMID: 791682
  61. Yeast promoters and lacZ fusions designed to study expression of cloned genes in yeast.
    Methods Enzymol. 1983;101:181-91 PMID: 6310321
  62. A temperature-sensitive N-glycosylation mutant of S. cerevisiae that behaves like a cell-cycle mutant.
    Exp Cell Res. 1984 Feb;150(2):309-13 PMID: 6363106
  63. Inhibition of the heat shock response and synthesis of glucose-regulated proteins in Ca2+-deprived rat hepatoma cells.
    Biochem Biophys Res Commun. 1985 Sep 16;131(2):868-76 PMID: 3931641
  64. A model for receptor-regulated calcium entry.
    Cell Calcium. 1986 Feb;7(1):1-12 PMID: 2420465
  65. Depletion of intracellular calcium stores by calcium ionophore A23187 induces the genes for glucose-regulated proteins in hamster fibroblasts.
    J Biol Chem. 1987 Sep 15;262(26):12801-5 PMID: 3114264
  66. Purification of a RAS-responsive adenylyl cyclase complex from Saccharomyces cerevisiae by use of an epitope addition method.
    Mol Cell Biol. 1988 May;8(5):2159-65 PMID: 2455217
  67. Mutational disruption of plasma membrane trafficking of Saccharomyces cerevisiae Yor1p, a homologue of mammalian multidrug resistance protein.
    Mol Cell Biol. 1999 Apr;19(4):2998-3009 PMID: 10082567
  68. Cloning of a novel four repeat protein related to voltage-gated sodium and calcium channels.
    FEBS Lett. 1999 Feb 26;445(2-3):231-6 PMID: 10094463
  69. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls.
    Genes Dev. 1999 May 15;13(10):1211-33 PMID: 10346810
  70. Induction of vacuolar Ca2+-ATPase and H+/Ca2+ exchange activity in yeast mutants lacking Pmr1, the Golgi Ca2+-ATPase.
    FEBS Lett. 1999 Jul 9;454(3):181-6 PMID: 10431803
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/21.10.2343
Published
2002-05-15
Pages
2343-53
Language
English
Region
England
NLM ID
8208664
PMCID
PMC126012
Subset
IM
Grants
NIGMS NIH HHS · R01 GM053082 · United States
NIGMS NIH HHS · GM53082 · United States
External Links
PubMed source DOI: 10.1093/emboj/21.10.2343 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: product@genelibs.com

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