Essential role of calcineurin in response to endoplasmic reticulum stress

Bonilla, Myriam; Nastase, Kristin K.; Cunningham, Kyle W.

doi:10.1093/emboj/21.10.2343

Cited by 255Endoplasmic Reticulum Stress and DiseaseIon Channels and ReceptorsFungal and yeast genetics research

Essential role of calcineurin in response to endoplasmic reticulum stress

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Bonilla, Myriam, Nastase, Kristin K., Cunningham, Kyle W.·2002·The EMBO Journal

DOI 10.1093/emboj/21.10.2343PMC PMC126012

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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.

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Calcineurin also promoted tolerance to terbinafine in C. albicans, to tunicamycin and dithiothreitol in S. cerevisiae, and to SDZ 90-215 in all these species.
“Calcineurin also promoted tolerance to terbinafine in C. albicans (58), to tunicamycin and dithiothreitol in S. cerevisiae (59, 60), and to SDZ 90-215 in all these species (61).”
From Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata (2026) · cites this paper as [59]
Treatment of fungal cells with azole antifungals led to an influx of extracellular Ca2+ that promoted the survival of fungi exposed to azole-induced stress.
“Treatment of fungal cells with azole antifungals led to an influx of extracellular Ca 2ϩ that promoted the survival of fungi exposed to azole-induced stress (16 -19).”
From Cch1 Restores Intracellular Ca2+ in Fungal Cells during Endoplasmic Reticulum Stress (2010) · cites this paper as [18]
There is broad conservation of cellular mechanisms to survive antifungal drug stress in fungal species.
“and suggest a broad conservation of cellular mechanisms to survive antifungal drug stress in fungal species.”
From The Rho1 GTPase-activating protein CgBem2 is required for survival of azole stress in Candida glabrata (2011) · cites this paper as [18]

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Miconazole induces aneuploidy-mediated tolerance in Candida albicans that is dependent on Hsp90 and calcineurin
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“Accumulation of unfolded proteins and inhibition of ergosterol synthesis in the endoplasmic reticulum stimulate an in ﬂ ux of Ca 2+ , which promotes cell survival by activating calcineurin (Bonilla et al., 2002).”
Background
Echinocandin tolerance and persistence in vitro are regulated by calcineurin signaling in Candida glabrata
Harrington, A. A., Nickels, T. J., & Cunningham, K. W. (2026) · mBio · doi:10.1128/mbio.02546-25 · Cited by 4 · see citing works
“Calcineurin also promoted tolerance to terbinafine in C. albicans (58), to tunicamycin and dithiothreitol in S. cerevisiae (59, 60), and to SDZ 90-215 in all these species (61).”
Self-citation

Authors: Bonilla, M., Nastase, K. K., & Cunningham, K. W.
Affiliations: Johns Hopkins University (US)
Corresponding author: Cunningham, Kyle W.
ORCID: Cunningham, Kyle W.
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2002-05-15
Volume: 21
Issue: 10
Pages: 2343-2353
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1093/emboj/21.10.2343
PMC: PMC126012
OpenAlex: W2121972996
Cited by: 255
References: 77
Citations by year: 2026: 2 · 2025: 6 · 2024: 9 · 2023: 6 · 2022: 12 · 2021: 5 · 2020: 10 · 2019: 5 · 2018: 3 · 2017: 14 · 2016: 10 · 2015: 12 · 2014: 21 · 2013: 10 · 2012: 23
FWCI: 5.21
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Institute of General Medical Sciences (GM53082, R01GM053082)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Keywords: calcineurin, endoplasmic reticulum stress, unfolded protein response, calcium influx, calmodulin, Ire1p, misfolded proteins, cell survival, fungal pathogens, Saccharomyces cerevisiae
MeSH terms: Antifungal Agents, Calmodulin, Cell Membrane, Cell Survival, DNA, Fungal, Endoplasmic Reticulum, Genotype, Saccharomyces cerevisiae, Stress, Mechanical, Tunicamycin, Blotting, Northern, Calcium Channels, Signal Transduction, Polymerase Chain Reaction, Protein Folding, Calcineurin, Calcium Signaling

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Essential role of calcineurin in response to endoplasmic reticulum stress

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