A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT Ras proteins function as conserved regulators of eukaryotic growth and differentiation and are essential signaling proteins orchestrating virulence in pathogenic fungi. Here, we report the identification of a novel N-terminal domain of the RasA protein in the filamentous fungus Aspergillus...

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Autores principales:	Qusai Al Abdallah, Tiffany S. Norton, Amy M. Hill, Lawrence L. LeClaire, Jarrod R. Fortwendel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Aspergillus Ras actin morphogenesis signal transduction Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/31d2993819814b138e397c2c9cb1dd17
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spelling	oai:doaj.org-article:31d2993819814b138e397c2c9cb1dd172021-11-15T15:22:03ZA Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mSphere.00234-162379-5042https://doaj.org/article/31d2993819814b138e397c2c9cb1dd172016-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00234-16https://doaj.org/toc/2379-5042ABSTRACT Ras proteins function as conserved regulators of eukaryotic growth and differentiation and are essential signaling proteins orchestrating virulence in pathogenic fungi. Here, we report the identification of a novel N-terminal domain of the RasA protein in the filamentous fungus Aspergillus fumigatus. Whereas this domain is absent in Ras homologs of higher eukaryotes, the N-terminal extension is conserved among fungi and is characterized by a short string of two to eight amino acids terminating in an invariant arginine. For this reason, we have termed the RasA N-terminal domain the invariant arginine domain (IRD). Through mutational analyses, the IRD was found to be essential for polarized morphogenesis and asexual development, with the invariant arginine residue being most essential. Although IRD truncation resulted in a nonfunctional Ras phenotype, IRD mutation was not associated with mislocalization of the RasA protein or significant changes in steady-state RasA activity levels. Mutation of the RasA IRD diminished protein kinase A (PKA) activation and resulted in decreased interaction with the Rho-type GTPase, Cdc42. Taken together, our findings reveal novel, fungus-specific mechanisms for Ras protein function and signal transduction. IMPORTANCE Aspergillus fumigatus is an important fungal pathogen against which limited treatments exist. During invasive disease, A. fumigatus hyphae grow in a highly polarized fashion, forming filaments that invade blood vessels and disseminate to distant sites. Once invasion and dissemination occur, mortality rates are high. We have previously shown that the Ras signaling pathway is an important regulator of the hyphal growth machinery supporting virulence in A. fumigatus. Here, we show that functional Ras signaling in A. fumigatus requires a novel, fungus-specific domain within the Ras protein. This domain is highly conserved among fungi, yet absent in higher eukaryotes, suggesting a potentially crucial difference in the regulation of Ras pathway activity between the human host and the fungal pathogen. Exploration of the mechanisms through which this domain regulates signaling could lead to novel antifungal therapies specifically targeting fungal Ras pathways.Qusai Al AbdallahTiffany S. NortonAmy M. HillLawrence L. LeClaireJarrod R. FortwendelAmerican Society for MicrobiologyarticleAspergillusRasactinmorphogenesissignal transductionMicrobiologyQR1-502ENmSphere, Vol 1, Iss 6 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus Ras actin morphogenesis signal transduction Microbiology QR1-502
spellingShingle	Aspergillus Ras actin morphogenesis signal transduction Microbiology QR1-502 Qusai Al Abdallah Tiffany S. Norton Amy M. Hill Lawrence L. LeClaire Jarrod R. Fortwendel A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT Ras proteins function as conserved regulators of eukaryotic growth and differentiation and are essential signaling proteins orchestrating virulence in pathogenic fungi. Here, we report the identification of a novel N-terminal domain of the RasA protein in the filamentous fungus Aspergillus fumigatus. Whereas this domain is absent in Ras homologs of higher eukaryotes, the N-terminal extension is conserved among fungi and is characterized by a short string of two to eight amino acids terminating in an invariant arginine. For this reason, we have termed the RasA N-terminal domain the invariant arginine domain (IRD). Through mutational analyses, the IRD was found to be essential for polarized morphogenesis and asexual development, with the invariant arginine residue being most essential. Although IRD truncation resulted in a nonfunctional Ras phenotype, IRD mutation was not associated with mislocalization of the RasA protein or significant changes in steady-state RasA activity levels. Mutation of the RasA IRD diminished protein kinase A (PKA) activation and resulted in decreased interaction with the Rho-type GTPase, Cdc42. Taken together, our findings reveal novel, fungus-specific mechanisms for Ras protein function and signal transduction. IMPORTANCE Aspergillus fumigatus is an important fungal pathogen against which limited treatments exist. During invasive disease, A. fumigatus hyphae grow in a highly polarized fashion, forming filaments that invade blood vessels and disseminate to distant sites. Once invasion and dissemination occur, mortality rates are high. We have previously shown that the Ras signaling pathway is an important regulator of the hyphal growth machinery supporting virulence in A. fumigatus. Here, we show that functional Ras signaling in A. fumigatus requires a novel, fungus-specific domain within the Ras protein. This domain is highly conserved among fungi, yet absent in higher eukaryotes, suggesting a potentially crucial difference in the regulation of Ras pathway activity between the human host and the fungal pathogen. Exploration of the mechanisms through which this domain regulates signaling could lead to novel antifungal therapies specifically targeting fungal Ras pathways.
format	article
author	Qusai Al Abdallah Tiffany S. Norton Amy M. Hill Lawrence L. LeClaire Jarrod R. Fortwendel
author_facet	Qusai Al Abdallah Tiffany S. Norton Amy M. Hill Lawrence L. LeClaire Jarrod R. Fortwendel
author_sort	Qusai Al Abdallah
title	A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	fungus-specific protein domain is essential for rasa-mediated morphogenetic signaling in <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/31d2993819814b138e397c2c9cb1dd17
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A Fungus-Specific Protein Domain Is Essential for RasA-Mediated Morphogenetic Signaling in <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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