Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> 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 th...

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Autores principales: Iaroslava Kos, Miranda J. Patterson, Sadri Znaidi, Despoina Kaloriti, Alessandra da Silva Dantas, Carmen M. Herrero-de-Dios, Christophe d’Enfert, Alistair J. P. Brown, Janet Quinn
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Publicado: American Society for Microbiology 2016
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spelling oai:doaj.org-article:22d63d835a5c45e88d190bf74bb3265c2021-11-15T15:41:41ZMechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency10.1128/mBio.00331-162150-7511https://doaj.org/article/22d63d835a5c45e88d190bf74bb3265c2016-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00331-16https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE Combinatorial stress-mediated synergistic killing represents a new unchartered area in the field of stress signaling. This phenomenon contrasts starkly with “stress cross-protection,” where exposure to one stress protects against subsequent exposure to a different stress. Previously we demonstrated that the pathogen Candida albicans is acutely sensitive to combinations of cationic and oxidative stresses, because the induction of H2O2-responsive genes is blocked in the presence of cationic stress. We reveal that this is due to novel mechanisms that delay activation of the Cap1 AP-1-like transcription factor, the major regulator of the H2O2-induced regulon. Cap1 becomes trapped in a partially oxidized form following simultaneous exposure to oxidative and cationic stresses. In addition, cationic stress promotes the interaction of Cap1 with the Crm1 nuclear export factor, thus inhibiting its nuclear accumulation. These mechanisms probably explain the potency of neutrophils, which employ multiple stresses to kill fungal pathogens.Iaroslava KosMiranda J. PattersonSadri ZnaidiDespoina KaloritiAlessandra da Silva DantasCarmen M. Herrero-de-DiosChristophe d’EnfertAlistair J. P. BrownJanet QuinnAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 2 (2016)
institution DOAJ
collection DOAJ
language EN
topic Microbiology
QR1-502
spellingShingle Microbiology
QR1-502
Iaroslava Kos
Miranda J. Patterson
Sadri Znaidi
Despoina Kaloriti
Alessandra da Silva Dantas
Carmen M. Herrero-de-Dios
Christophe d’Enfert
Alistair J. P. Brown
Janet Quinn
Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency
description 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. IMPORTANCE Combinatorial stress-mediated synergistic killing represents a new unchartered area in the field of stress signaling. This phenomenon contrasts starkly with “stress cross-protection,” where exposure to one stress protects against subsequent exposure to a different stress. Previously we demonstrated that the pathogen Candida albicans is acutely sensitive to combinations of cationic and oxidative stresses, because the induction of H2O2-responsive genes is blocked in the presence of cationic stress. We reveal that this is due to novel mechanisms that delay activation of the Cap1 AP-1-like transcription factor, the major regulator of the H2O2-induced regulon. Cap1 becomes trapped in a partially oxidized form following simultaneous exposure to oxidative and cationic stresses. In addition, cationic stress promotes the interaction of Cap1 with the Crm1 nuclear export factor, thus inhibiting its nuclear accumulation. These mechanisms probably explain the potency of neutrophils, which employ multiple stresses to kill fungal pathogens.
format article
author Iaroslava Kos
Miranda J. Patterson
Sadri Znaidi
Despoina Kaloriti
Alessandra da Silva Dantas
Carmen M. Herrero-de-Dios
Christophe d’Enfert
Alistair J. P. Brown
Janet Quinn
author_facet Iaroslava Kos
Miranda J. Patterson
Sadri Znaidi
Despoina Kaloriti
Alessandra da Silva Dantas
Carmen M. Herrero-de-Dios
Christophe d’Enfert
Alistair J. P. Brown
Janet Quinn
author_sort Iaroslava Kos
title Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency
title_short Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency
title_full Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency
title_fullStr Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency
title_full_unstemmed Mechanisms Underlying the Delayed Activation of the Cap1 Transcription Factor in <named-content content-type="genus-species">Candida albicans</named-content> following Combinatorial Oxidative and Cationic Stress Important for Phagocytic Potency
title_sort mechanisms underlying the delayed activation of the cap1 transcription factor in <named-content content-type="genus-species">candida albicans</named-content> following combinatorial oxidative and cationic stress important for phagocytic potency
publisher American Society for Microbiology
publishDate 2016
url https://doaj.org/article/22d63d835a5c45e88d190bf74bb3265c
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