Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs

ABSTRACT In all eukaryotic kingdoms, mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses to environmental cues. These MAPKs are activated by phosphorylation at highly conserved threonine and tyrosine residues in response to specific inputs, leading to their accumulati...

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Autores principales:	Carmen Herrero-de-Dios, Alison M. Day, Anna T. Tillmann, Stavroula L. Kastora, David Stead, Paula S. Salgado, Janet Quinn, Alistair J. P. Brown
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Candida albicans MAP kinase signaling nitrosative stress Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f5b73d7ef4194195a32a24d030a681c5
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spelling	oai:doaj.org-article:f5b73d7ef4194195a32a24d030a681c52021-11-15T15:53:26ZRedox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs10.1128/mBio.02229-172150-7511https://doaj.org/article/f5b73d7ef4194195a32a24d030a681c52018-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02229-17https://doaj.org/toc/2150-7511ABSTRACT In all eukaryotic kingdoms, mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses to environmental cues. These MAPKs are activated by phosphorylation at highly conserved threonine and tyrosine residues in response to specific inputs, leading to their accumulation in the nucleus and the activation of their downstream targets. A specific MAP kinase can regulate different downstream targets depending on the nature of the input signal, thereby raising a key question: what defines the stress-specific outputs of MAP kinases? We find that the Hog1 MAPK contributes to nitrosative-stress resistance in Candida albicans even though it displays minimal stress-induced phosphorylation under these conditions. We show that Hog1 becomes oxidized in response to nitrosative stress, accumulates in the nucleus, and regulates the nitrosative stress-induced transcriptome. Mutation of specific cysteine residues revealed that C156 and C161 function together to promote stress resistance, Hog1-mediated nitrosative-stress-induced gene expression, resistance to phagocytic killing, and C. albicans virulence. We propose that the oxidation of Hog1, rather than its phosphorylation, contributes to the nitrosative-stress-specific responses of this MAP kinase. IMPORTANCE Mitogen-activated protein kinases play key roles in the responses of eukaryotic cells to extracellular signals and are critical for environmental-stress resistance. The widely accepted paradigm is that MAP kinases are activated by phosphorylation, which then triggers their nuclear accumulation and the activation of target proteins and genes that promote cellular adaptation. Our data suggest that alternative forms of posttranslational modification can modulate MAP kinase functionality in Candida albicans. We demonstrate that Hog1 is not significantly phosphorylated in response to nitrosative stress, yet it displays nuclear accumulation and contributes to the global transcriptional response to this stress, as well as promoting nitrosative-stress resistance. Instead, nitrosative stress triggers changes in the redox status of Hog1. We also show that specific Hog1 cysteine residues influence its activation of stress genes. Therefore, alternative posttranslational modifications appear to regulate the stress-specific outputs of MAP kinases.Carmen Herrero-de-DiosAlison M. DayAnna T. TillmannStavroula L. KastoraDavid SteadPaula S. SalgadoJanet QuinnAlistair J. P. BrownAmerican Society for MicrobiologyarticleCandida albicansMAP kinase signalingnitrosative stressMicrobiologyQR1-502ENmBio, Vol 9, Iss 2 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Candida albicans MAP kinase signaling nitrosative stress Microbiology QR1-502
spellingShingle	Candida albicans MAP kinase signaling nitrosative stress Microbiology QR1-502 Carmen Herrero-de-Dios Alison M. Day Anna T. Tillmann Stavroula L. Kastora David Stead Paula S. Salgado Janet Quinn Alistair J. P. Brown Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
description	ABSTRACT In all eukaryotic kingdoms, mitogen-activated protein kinases (MAPKs) play critical roles in cellular responses to environmental cues. These MAPKs are activated by phosphorylation at highly conserved threonine and tyrosine residues in response to specific inputs, leading to their accumulation in the nucleus and the activation of their downstream targets. A specific MAP kinase can regulate different downstream targets depending on the nature of the input signal, thereby raising a key question: what defines the stress-specific outputs of MAP kinases? We find that the Hog1 MAPK contributes to nitrosative-stress resistance in Candida albicans even though it displays minimal stress-induced phosphorylation under these conditions. We show that Hog1 becomes oxidized in response to nitrosative stress, accumulates in the nucleus, and regulates the nitrosative stress-induced transcriptome. Mutation of specific cysteine residues revealed that C156 and C161 function together to promote stress resistance, Hog1-mediated nitrosative-stress-induced gene expression, resistance to phagocytic killing, and C. albicans virulence. We propose that the oxidation of Hog1, rather than its phosphorylation, contributes to the nitrosative-stress-specific responses of this MAP kinase. IMPORTANCE Mitogen-activated protein kinases play key roles in the responses of eukaryotic cells to extracellular signals and are critical for environmental-stress resistance. The widely accepted paradigm is that MAP kinases are activated by phosphorylation, which then triggers their nuclear accumulation and the activation of target proteins and genes that promote cellular adaptation. Our data suggest that alternative forms of posttranslational modification can modulate MAP kinase functionality in Candida albicans. We demonstrate that Hog1 is not significantly phosphorylated in response to nitrosative stress, yet it displays nuclear accumulation and contributes to the global transcriptional response to this stress, as well as promoting nitrosative-stress resistance. Instead, nitrosative stress triggers changes in the redox status of Hog1. We also show that specific Hog1 cysteine residues influence its activation of stress genes. Therefore, alternative posttranslational modifications appear to regulate the stress-specific outputs of MAP kinases.
format	article
author	Carmen Herrero-de-Dios Alison M. Day Anna T. Tillmann Stavroula L. Kastora David Stead Paula S. Salgado Janet Quinn Alistair J. P. Brown
author_facet	Carmen Herrero-de-Dios Alison M. Day Anna T. Tillmann Stavroula L. Kastora David Stead Paula S. Salgado Janet Quinn Alistair J. P. Brown
author_sort	Carmen Herrero-de-Dios
title	Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
title_short	Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
title_full	Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
title_fullStr	Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
title_full_unstemmed	Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs
title_sort	redox regulation, rather than stress-induced phosphorylation, of a hog1 mitogen-activated protein kinase modulates its nitrosative-stress-specific outputs
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/f5b73d7ef4194195a32a24d030a681c5
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Redox Regulation, Rather than Stress-Induced Phosphorylation, of a Hog1 Mitogen-Activated Protein Kinase Modulates Its Nitrosative-Stress-Specific Outputs

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