Cyclic AMP pathway activation and extracellular zinc induce rapid intracellular zinc mobilization in Candida albicans

Lasse  Kjellerup; Anne-Marie L.  Winther; Duncan Wilson; Anja T. Fuglsang

doi:10.3389/fmicb.2018.00502

Cyclic AMP pathway activation and extracellular zinc induce rapid intracellular zinc mobilization in Candida albicans

Lasse Kjellerup, Anne-Marie L. Winther, Duncan Wilson, Anja T. Fuglsang

Medical Sciences

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Abstract

Zinc is an essential micronutrient, required for a range of zinc dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo 5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans. We provide evidence for a link between cyclic AMP/PKA- and zinc- signaling in this major human fungal pathogen. Glucose stimulation, which triggers a cyclic AMP spike in this fungus resulted in rapid intracellular zinc mobilization and this “zinc flux” could be stimulated with phosphodiesterase inhibitors and blocked via inhibition of adenylate cyclase or PKA. A similar mobilization of intracellular zinc was generated by stimulation of cells with extracellular zinc and this effect could be reversed with the chelator EDTA. However zinc-induced zinc flux was found to be cyclic AMP independent. In summary, we show that activation of the cyclic AMP/PKA pathway triggers intracellular zinc mobilization in a fungus. To our knowledge, this is the first described link between cyclic AMP signaling and zinc homeostasis in a human fungal pathogen.

Original language	English
Article number	502
Number of pages	10
Journal	Frontiers in Microbiology
Volume	9
Early online date	21 Mar 2018
DOIs	https://doi.org/10.3389/fmicb.2018.00502
Publication status	Published - 21 Mar 2018

Bibliographical note

LK was supported by Innovation Fund Denmark, DK (4019-00019B). Pcovery ApS received funding from Wellcome Trust, Research Councils, UK (100480/Z/12), Novo Seeds, DK and Boehringer Ingelheim Venture Fund, D. DW is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (102549/Z/13/Z), the Medical Research Council and University of Aberdeen (MR/N006364/1) and received support from a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z). The funders had no part in study design, data collection and interpretation, or the decision to submit the work for publication.

Keywords

cAMP Zinc
candida albicans
signaling
ER
ion homeostasis
bioimaging

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10.3389/fmicb.2018.00502Licence: CC BY

Cyclic AMP Pathway Activation and Extracellular Zinc Induce Rapid Intracellular Zinc Mobilization in Candida albicans
Copyright © 2018 Kjellerup, Winther, Wilson and Fuglsang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. https://creativecommons.org/licenses/by/4.0/
Final published version, 2.4 MBLicence: CC BY

Cite this

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title = "Cyclic AMP pathway activation and extracellular zinc induce rapid intracellular zinc mobilization in Candida albicans",

abstract = "Zinc is an essential micronutrient, required for a range of zinc dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo 5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans. We provide evidence for a link between cyclic AMP/PKA- and zinc- signaling in this major human fungal pathogen. Glucose stimulation, which triggers a cyclic AMP spike in this fungus resulted in rapid intracellular zinc mobilization and this “zinc flux” could be stimulated with phosphodiesterase inhibitors and blocked via inhibition of adenylate cyclase or PKA. A similar mobilization of intracellular zinc was generated by stimulation of cells with extracellular zinc and this effect could be reversed with the chelator EDTA. However zinc-induced zinc flux was found to be cyclic AMP independent. In summary, we show that activation of the cyclic AMP/PKA pathway triggers intracellular zinc mobilization in a fungus. To our knowledge, this is the first described link between cyclic AMP signaling and zinc homeostasis in a human fungal pathogen.",

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author = "Lasse Kjellerup and Winther, {Anne-Marie L.} and Duncan Wilson and Fuglsang, {Anja T.}",

note = "LK was supported by Innovation Fund Denmark, DK (4019-00019B). Pcovery ApS received funding from Wellcome Trust, Research Councils, UK (100480/Z/12), Novo Seeds, DK and Boehringer Ingelheim Venture Fund, D. DW is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (102549/Z/13/Z), the Medical Research Council and University of Aberdeen (MR/N006364/1) and received support from a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z). The funders had no part in study design, data collection and interpretation, or the decision to submit the work for publication. ",

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AU - Winther, Anne-Marie L.

AU - Wilson, Duncan

AU - Fuglsang, Anja T.

N1 - LK was supported by Innovation Fund Denmark, DK (4019-00019B). Pcovery ApS received funding from Wellcome Trust, Research Councils, UK (100480/Z/12), Novo Seeds, DK and Boehringer Ingelheim Venture Fund, D. DW is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (102549/Z/13/Z), the Medical Research Council and University of Aberdeen (MR/N006364/1) and received support from a Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology (097377/Z/11/Z). The funders had no part in study design, data collection and interpretation, or the decision to submit the work for publication.

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N2 - Zinc is an essential micronutrient, required for a range of zinc dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo 5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans. We provide evidence for a link between cyclic AMP/PKA- and zinc- signaling in this major human fungal pathogen. Glucose stimulation, which triggers a cyclic AMP spike in this fungus resulted in rapid intracellular zinc mobilization and this “zinc flux” could be stimulated with phosphodiesterase inhibitors and blocked via inhibition of adenylate cyclase or PKA. A similar mobilization of intracellular zinc was generated by stimulation of cells with extracellular zinc and this effect could be reversed with the chelator EDTA. However zinc-induced zinc flux was found to be cyclic AMP independent. In summary, we show that activation of the cyclic AMP/PKA pathway triggers intracellular zinc mobilization in a fungus. To our knowledge, this is the first described link between cyclic AMP signaling and zinc homeostasis in a human fungal pathogen.

AB - Zinc is an essential micronutrient, required for a range of zinc dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo 5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans. We provide evidence for a link between cyclic AMP/PKA- and zinc- signaling in this major human fungal pathogen. Glucose stimulation, which triggers a cyclic AMP spike in this fungus resulted in rapid intracellular zinc mobilization and this “zinc flux” could be stimulated with phosphodiesterase inhibitors and blocked via inhibition of adenylate cyclase or PKA. A similar mobilization of intracellular zinc was generated by stimulation of cells with extracellular zinc and this effect could be reversed with the chelator EDTA. However zinc-induced zinc flux was found to be cyclic AMP independent. In summary, we show that activation of the cyclic AMP/PKA pathway triggers intracellular zinc mobilization in a fungus. To our knowledge, this is the first described link between cyclic AMP signaling and zinc homeostasis in a human fungal pathogen.

KW - cAMP Zinc

KW - candida albicans

KW - signaling

KW - ER

KW - ion homeostasis

KW - bioimaging

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DO - 10.3389/fmicb.2018.00502

M3 - Article

SN - 1664-302X

VL - 9

JO - Frontiers in Microbiology

JF - Frontiers in Microbiology

M1 - 502

ER -

Cyclic AMP pathway activation and extracellular zinc induce rapid intracellular zinc mobilization in Candida albicans

Abstract

Bibliographical note

Keywords

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