Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency

Iaroslava Kos, Miranda Patterson, Sadri Znaidi, Despoina Kaloriti, Alessandra da Silva Dantas, Carmen Maria Herrero De Dios, Christophe d'Enfert, Alistair James Petersen Brown, Janet Quinn

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Abstract

Following phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogen Candida albicans by “stress pathway interference.” Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression in C. albicans, is significantly delayed in response to combinatorial stress treatments and to high levels of H2O2. Cap1 is normally oxidized in response to H2O2; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H2O2, Cap1 becomes trapped in a partially oxidized form, Cap1OX-1. Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1OX-1 readily accumulates in the nucleus and binds to target genes following high-H2O2 stress, the nuclear accumulation of Cap1OX-1 following combinatorial H2O2 and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival of C. albicans within the host.
Original languageEnglish
Article numbere00331-16
JournalmBio
Volume7
Issue number2
DOIs
Publication statusPublished - 29 Mar 2016

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Candida albicans
Oxidative Stress
Cell Nucleus Active Transport
Reactive Oxygen Species
Gene Expression
Weapons
Regulator Genes
Masks
Phagocytosis
Genes
Transcription Factors
Antioxidants
Candida albicans AP1 protein

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Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency. / Kos, Iaroslava; Patterson, Miranda; Znaidi, Sadri; Kaloriti, Despoina; da Silva Dantas, Alessandra; Herrero De Dios, Carmen Maria; d'Enfert, Christophe; Brown, Alistair James Petersen; Quinn, Janet.

In: mBio, Vol. 7, No. 2, e00331-16, 29.03.2016.

Research output: Contribution to journalArticle

Kos, Iaroslava ; Patterson, Miranda ; Znaidi, Sadri ; Kaloriti, Despoina ; da Silva Dantas, Alessandra ; Herrero De Dios, Carmen Maria ; d'Enfert, Christophe ; Brown, Alistair James Petersen ; Quinn, Janet. / Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency. In: mBio. 2016 ; Vol. 7, No. 2.
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title = "Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency",
abstract = "Following phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogen Candida albicans by “stress pathway interference.” Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression in C. albicans, is significantly delayed in response to combinatorial stress treatments and to high levels of H2O2. Cap1 is normally oxidized in response to H2O2; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H2O2, Cap1 becomes trapped in a partially oxidized form, Cap1OX-1. Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1OX-1 readily accumulates in the nucleus and binds to target genes following high-H2O2 stress, the nuclear accumulation of Cap1OX-1 following combinatorial H2O2 and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival of C. albicans within the host.",
author = "Iaroslava Kos and Miranda Patterson and Sadri Znaidi and Despoina Kaloriti and {da Silva Dantas}, Alessandra and {Herrero De Dios}, {Carmen Maria} and Christophe d'Enfert and Brown, {Alistair James Petersen} and Janet Quinn",
note = "ACKNOWLEDGMENTS We are grateful to Brian Morgan and Elizabeth Veal for insightful discussions, M{\'e}lanie Ikeh for experimental assistance, and Scott Moye-Rowley (University of Iowa) for the gift of the anti-Cap1 antibody. This work was funded by the NIHR Newcastle Biomedical Research Centre (I.K.), a BBSRC DTG studentship (M.J.P.), the Wellcome Trust (grants 089930 and 097377 to J.Q. and 080088 and 097377 to A.J.P.B.), the BBSRC (grants BB/K016393/1 to J.Q. and BB/F00513X/1 and BB/K017365/1 to A.J.P.B.), the European Research Council (STRIFE Advanced grant ERC-2009-AdG-249793 to A.J.P.B.), the ANR (grant CANDIHUB, ANR-14-CE14-0018-01, to C.D.), and the French Government’s Investissement d’Avenir program (grant IBEID, ANR-10-LABX-62-IBEID, to C.D.). FUNDING INFORMATION This work, including the efforts of Alistair J.P. Brown, was funded by Wellcome Trust (097377 and 080088). This work, including the efforts of Janet Quinn, was funded by Wellcome Trust (097377 and 089930). This work, including the efforts of Alistair J.P. Brown, was funded by EC European Research Council (ERC) (ERC-2009-AdG-249793). This work, including the efforts of Alistair J.P. Brown, was funded by Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F00513X/1 and BB/K017365/1). This work, including the efforts of Janet Quinn, was funded by Biotechnology and Biological Sciences Research Council (BBSRC) (BB/K016393/1). This work, including the efforts of Christophe d’Enfert, was funded by Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0018-01 and ANR-10-LABX-62-IBEID).",
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T1 - Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in Candida albicans following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency

AU - Kos, Iaroslava

AU - Patterson, Miranda

AU - Znaidi, Sadri

AU - Kaloriti, Despoina

AU - da Silva Dantas, Alessandra

AU - Herrero De Dios, Carmen Maria

AU - d'Enfert, Christophe

AU - Brown, Alistair James Petersen

AU - Quinn, Janet

N1 - ACKNOWLEDGMENTS We are grateful to Brian Morgan and Elizabeth Veal for insightful discussions, Mélanie Ikeh for experimental assistance, and Scott Moye-Rowley (University of Iowa) for the gift of the anti-Cap1 antibody. This work was funded by the NIHR Newcastle Biomedical Research Centre (I.K.), a BBSRC DTG studentship (M.J.P.), the Wellcome Trust (grants 089930 and 097377 to J.Q. and 080088 and 097377 to A.J.P.B.), the BBSRC (grants BB/K016393/1 to J.Q. and BB/F00513X/1 and BB/K017365/1 to A.J.P.B.), the European Research Council (STRIFE Advanced grant ERC-2009-AdG-249793 to A.J.P.B.), the ANR (grant CANDIHUB, ANR-14-CE14-0018-01, to C.D.), and the French Government’s Investissement d’Avenir program (grant IBEID, ANR-10-LABX-62-IBEID, to C.D.). FUNDING INFORMATION This work, including the efforts of Alistair J.P. Brown, was funded by Wellcome Trust (097377 and 080088). This work, including the efforts of Janet Quinn, was funded by Wellcome Trust (097377 and 089930). This work, including the efforts of Alistair J.P. Brown, was funded by EC European Research Council (ERC) (ERC-2009-AdG-249793). This work, including the efforts of Alistair J.P. Brown, was funded by Biotechnology and Biological Sciences Research Council (BBSRC) (BB/F00513X/1 and BB/K017365/1). This work, including the efforts of Janet Quinn, was funded by Biotechnology and Biological Sciences Research Council (BBSRC) (BB/K016393/1). This work, including the efforts of Christophe d’Enfert, was funded by Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0018-01 and ANR-10-LABX-62-IBEID).

PY - 2016/3/29

Y1 - 2016/3/29

N2 - Following phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogen Candida albicans by “stress pathway interference.” Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression in C. albicans, is significantly delayed in response to combinatorial stress treatments and to high levels of H2O2. Cap1 is normally oxidized in response to H2O2; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H2O2, Cap1 becomes trapped in a partially oxidized form, Cap1OX-1. Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1OX-1 readily accumulates in the nucleus and binds to target genes following high-H2O2 stress, the nuclear accumulation of Cap1OX-1 following combinatorial H2O2 and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival of C. albicans within the host.

AB - Following phagocytosis, microbes are exposed to an array of antimicrobial weapons that include reactive oxygen species (ROS) and cationic fluxes. This is significant as combinations of oxidative and cationic stresses are much more potent than the corresponding single stresses, triggering the synergistic killing of the fungal pathogen Candida albicans by “stress pathway interference.” Previously we demonstrated that combinatorial oxidative plus cationic stress triggers a dramatic increase in intracellular ROS levels compared to oxidative stress alone. Here we show that activation of Cap1, the major regulator of antioxidant gene expression in C. albicans, is significantly delayed in response to combinatorial stress treatments and to high levels of H2O2. Cap1 is normally oxidized in response to H2O2; this masks the nuclear export sequence, resulting in the rapid nuclear accumulation of Cap1 and the induction of Cap1-dependent genes. Here we demonstrate that following exposure of cells to combinatorial stress or to high levels of H2O2, Cap1 becomes trapped in a partially oxidized form, Cap1OX-1. Notably, Cap1-dependent gene expression is not induced when Cap1 is in this partially oxidized form. However, while Cap1OX-1 readily accumulates in the nucleus and binds to target genes following high-H2O2 stress, the nuclear accumulation of Cap1OX-1 following combinatorial H2O2 and NaCl stress is delayed due to a cationic stress-enhanced interaction with the Crm1 nuclear export factor. These findings define novel mechanisms that delay activation of the Cap1 transcription factor, thus preventing the rapid activation of the stress responses vital for the survival of C. albicans within the host.

U2 - 10.1128/mBio.00331-16

DO - 10.1128/mBio.00331-16

M3 - Article

VL - 7

JO - mBio

JF - mBio

SN - 2161-2129

IS - 2

M1 - e00331-16

ER -