Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>

ABSTRACT Antofine, a phenanthroindolizidine alkaloid, is a bioactive natural product isolated from milkweeds that exhibits numerous biological activities, including anticancer, antimicrobial, antiviral, and anti-inflammatory properties. However, the direct targets and mode of action of antofine have...

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Autores principales:	Christopher Mogg, Christopher Bonner, Li Wang, Johann Schernthaner, Myron Smith, Darrell Desveaux, Rajagopal Subramaniam
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Fusarium drug targets rapamycin Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/10ea5efdd98a4eb49f904a02923f0d91
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spelling	oai:doaj.org-article:10ea5efdd98a4eb49f904a02923f0d912021-11-15T15:55:24ZGenomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>10.1128/mBio.00792-192150-7511https://doaj.org/article/10ea5efdd98a4eb49f904a02923f0d912019-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00792-19https://doaj.org/toc/2150-7511ABSTRACT Antofine, a phenanthroindolizidine alkaloid, is a bioactive natural product isolated from milkweeds that exhibits numerous biological activities, including anticancer, antimicrobial, antiviral, and anti-inflammatory properties. However, the direct targets and mode of action of antofine have not been determined. In this report, we show that antofine displays antifungal properties against the phytopathogen Fusarium graminearum, the cause of Fusarium head blight disease (FHB). FHB does devastating damage to agriculture, causing billions of dollars in economic losses annually. We therefore sought to understand the mode of action of antofine in F. graminearum using insights from yeast chemical genomic screens. We used haploinsufficiency profiling (HIP) to identify putative targets of antofine in yeast and identified three candidate targets, two of which had homologs in F. graminearum. The Fusarium homologues of two targets, glutamate dehydrogenase (FgGDH) and resistance to rapamycin deletion 2 (FgRRD2), can bind antofine. Of the two genes, only the Fgrrd2 knockout displayed a loss of virulence in wheat, indicating that RRD2 is an antivirulence target of antofine in F. graminearum. Mechanistically, we demonstrate that antofine disrupts the interaction between FgRRD2 and FgTap42, which is part of the Tap42-phosphatase complex in the target of rapamycin (TOR) signaling pathway, a central regulator of cell growth in eukaryotes and a pathway of extensive study for controlling numerous pathologies. IMPORTANCE Fusarium head blight caused by the fungal pathogen Fusarium graminearum is a devastating disease of cereal crops worldwide, with limited effective chemical treatments available. Here we show that the natural alkaloid compound antofine can inhibit fusarium head blight in wheat. Using yeast genomic screening, we identified the TOR pathway component RRD2 as a target of antofine that is also required for F. graminearum pathogenicity.Christopher MoggChristopher BonnerLi WangJohann SchernthanerMyron SmithDarrell DesveauxRajagopal SubramaniamAmerican Society for MicrobiologyarticleFusariumdrug targetsrapamycinMicrobiologyQR1-502ENmBio, Vol 10, Iss 3 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fusarium drug targets rapamycin Microbiology QR1-502
spellingShingle	Fusarium drug targets rapamycin Microbiology QR1-502 Christopher Mogg Christopher Bonner Li Wang Johann Schernthaner Myron Smith Darrell Desveaux Rajagopal Subramaniam Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>
description	ABSTRACT Antofine, a phenanthroindolizidine alkaloid, is a bioactive natural product isolated from milkweeds that exhibits numerous biological activities, including anticancer, antimicrobial, antiviral, and anti-inflammatory properties. However, the direct targets and mode of action of antofine have not been determined. In this report, we show that antofine displays antifungal properties against the phytopathogen Fusarium graminearum, the cause of Fusarium head blight disease (FHB). FHB does devastating damage to agriculture, causing billions of dollars in economic losses annually. We therefore sought to understand the mode of action of antofine in F. graminearum using insights from yeast chemical genomic screens. We used haploinsufficiency profiling (HIP) to identify putative targets of antofine in yeast and identified three candidate targets, two of which had homologs in F. graminearum. The Fusarium homologues of two targets, glutamate dehydrogenase (FgGDH) and resistance to rapamycin deletion 2 (FgRRD2), can bind antofine. Of the two genes, only the Fgrrd2 knockout displayed a loss of virulence in wheat, indicating that RRD2 is an antivirulence target of antofine in F. graminearum. Mechanistically, we demonstrate that antofine disrupts the interaction between FgRRD2 and FgTap42, which is part of the Tap42-phosphatase complex in the target of rapamycin (TOR) signaling pathway, a central regulator of cell growth in eukaryotes and a pathway of extensive study for controlling numerous pathologies. IMPORTANCE Fusarium head blight caused by the fungal pathogen Fusarium graminearum is a devastating disease of cereal crops worldwide, with limited effective chemical treatments available. Here we show that the natural alkaloid compound antofine can inhibit fusarium head blight in wheat. Using yeast genomic screening, we identified the TOR pathway component RRD2 as a target of antofine that is also required for F. graminearum pathogenicity.
format	article
author	Christopher Mogg Christopher Bonner Li Wang Johann Schernthaner Myron Smith Darrell Desveaux Rajagopal Subramaniam
author_facet	Christopher Mogg Christopher Bonner Li Wang Johann Schernthaner Myron Smith Darrell Desveaux Rajagopal Subramaniam
author_sort	Christopher Mogg
title	Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>
title_short	Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>
title_full	Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>
title_fullStr	Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>
title_full_unstemmed	Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>
title_sort	genomic identification of the tor signaling pathway as a target of the plant alkaloid antofine in the phytopathogen <named-content content-type="genus-species">fusarium graminearum</named-content>
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/10ea5efdd98a4eb49f904a02923f0d91
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Genomic Identification of the TOR Signaling Pathway as a Target of the Plant Alkaloid Antofine in the Phytopathogen <named-content content-type="genus-species">Fusarium graminearum</named-content>

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