<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence

ABSTRACT G-protein coupled receptors (GPCRs) are extracellular signaling receptors that sense environmental cues. Fungi sense their environment primarily through GPCR-mediated signaling pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. Aspergil...

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Autores principales:	Aílton Pereira da Costa Filho, Guilherme Thomaz Pereira Brancini, Patrícia Alves de Castro, Clara Valero, Jaire Alves Ferreira Filho, Lilian Pereira Silva, Marina Campos Rocha, Iran Malavazi, João Guilherme de Moraes Pontes, Taícia Fill, Roberto Nascimento Silva, Fausto Almeida, Jacob L. Steenwyk, Antonis Rokas, Thaila F. dos Reis, Laure N. A. Ries, Gustavo H. Goldman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Aspergillus fumigatus G-protein coupled receptor cell wall secondary metabolites virulence Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7c5c7d0d09484c4fbc96731559319dc3
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id	oai:doaj.org-article:7c5c7d0d09484c4fbc96731559319dc3
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus G-protein coupled receptor cell wall secondary metabolites virulence Microbiology QR1-502
spellingShingle	Aspergillus fumigatus G-protein coupled receptor cell wall secondary metabolites virulence Microbiology QR1-502 Aílton Pereira da Costa Filho Guilherme Thomaz Pereira Brancini Patrícia Alves de Castro Clara Valero Jaire Alves Ferreira Filho Lilian Pereira Silva Marina Campos Rocha Iran Malavazi João Guilherme de Moraes Pontes Taícia Fill Roberto Nascimento Silva Fausto Almeida Jacob L. Steenwyk Antonis Rokas Thaila F. dos Reis Laure N. A. Ries Gustavo H. Goldman <named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence
description	ABSTRACT G-protein coupled receptors (GPCRs) are extracellular signaling receptors that sense environmental cues. Fungi sense their environment primarily through GPCR-mediated signaling pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. Aspergillus fumigatus is an important human pathogen that causes aspergillosis, a heterogeneous group of diseases that present a wide range of clinical manifestations. Here, we investigate in detail the role of the GPCRs GprM and GprJ in growth and gene expression. GprM and GprJ are important for melanin production and the regulation of the cell wall integrity (CWI) pathway. Overexpression of gprM and gprJ causes a 20 and 50% reduction in growth rate compared to the wild-type (WT) strain and increases sensitivity to cell wall-damaging agents. Phosphorylation of the CWI protein kinase MpkA is increased in the ΔgprM and ΔgprJ strains and decreased in the overexpression mutants compared to the WT strain. Furthermore, differences in cell wall polysaccharide concentrations and organization were observed in these strains. Transcriptome sequencing suggests that GprM and GprJ negatively regulate genes encoding secondary metabolites (SMs). Mass spectrometry analysis confirmed that the production of fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, and fumitremorgin is reduced in the ΔgprM and ΔgprJ strains, at least partially through the activation of MpkA. Overexpression of grpM also resulted in the regulation of many transcription factors, with AsgA predicted to function downstream of GprM and MpkA signaling. Finally, we show that the ΔgprM and ΔgprJ mutants are reduced in virulence in the Galleria mellonella insect model of invasive aspergillosis. IMPORTANCE A. fumigatus is the main etiological agent of invasive pulmonary aspergillosis, a life-threatening fungal disease that occurs in severely immunocompromised humans. Withstanding the host environment is essential for A. fumigatus virulence, and sensing of extracellular cues occurs primarily through G-protein coupled receptors (GPCRs) that activate signal transduction pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. The A. fumigatus genome encodes 15 putative classical GPCRs, with only three having been functionally characterized to date. In this work, we show that the two GPCRs GprM and GprJ regulate the phosphorylation of the mitogen-activated protein kinase MpkA and thus control the regulation of the cell wall integrity pathway. GprM and GprJ are also involved in the regulation of the production of the secondary metabolites fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, melanin, and fumitremorgin, and this regulation partially occurs through the activation of MpkA. Furthermore, GprM and GprJ are important for virulence in the insect model Galleria mellonella. This work therefore functionally characterizes two GPCRs and shows how they regulate several intracellular pathways that have been shown to be crucial for A. fumigatus virulence.
format	article
author	Aílton Pereira da Costa Filho Guilherme Thomaz Pereira Brancini Patrícia Alves de Castro Clara Valero Jaire Alves Ferreira Filho Lilian Pereira Silva Marina Campos Rocha Iran Malavazi João Guilherme de Moraes Pontes Taícia Fill Roberto Nascimento Silva Fausto Almeida Jacob L. Steenwyk Antonis Rokas Thaila F. dos Reis Laure N. A. Ries Gustavo H. Goldman
author_facet	Aílton Pereira da Costa Filho Guilherme Thomaz Pereira Brancini Patrícia Alves de Castro Clara Valero Jaire Alves Ferreira Filho Lilian Pereira Silva Marina Campos Rocha Iran Malavazi João Guilherme de Moraes Pontes Taícia Fill Roberto Nascimento Silva Fausto Almeida Jacob L. Steenwyk Antonis Rokas Thaila F. dos Reis Laure N. A. Ries Gustavo H. Goldman
author_sort	Aílton Pereira da Costa Filho
title	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence
title_short	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence
title_full	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence
title_fullStr	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence
title_full_unstemmed	<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence
title_sort	<named-content content-type="genus-species">aspergillus fumigatus</named-content> g-protein coupled receptors gprm and gprj are important for the regulation of the cell wall integrity pathway, secondary metabolite production, and virulence
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/7c5c7d0d09484c4fbc96731559319dc3
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spelling	oai:doaj.org-article:7c5c7d0d09484c4fbc96731559319dc32021-11-15T16:19:07Z<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence10.1128/mBio.02458-202150-7511https://doaj.org/article/7c5c7d0d09484c4fbc96731559319dc32020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02458-20https://doaj.org/toc/2150-7511ABSTRACT G-protein coupled receptors (GPCRs) are extracellular signaling receptors that sense environmental cues. Fungi sense their environment primarily through GPCR-mediated signaling pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. Aspergillus fumigatus is an important human pathogen that causes aspergillosis, a heterogeneous group of diseases that present a wide range of clinical manifestations. Here, we investigate in detail the role of the GPCRs GprM and GprJ in growth and gene expression. GprM and GprJ are important for melanin production and the regulation of the cell wall integrity (CWI) pathway. Overexpression of gprM and gprJ causes a 20 and 50% reduction in growth rate compared to the wild-type (WT) strain and increases sensitivity to cell wall-damaging agents. Phosphorylation of the CWI protein kinase MpkA is increased in the ΔgprM and ΔgprJ strains and decreased in the overexpression mutants compared to the WT strain. Furthermore, differences in cell wall polysaccharide concentrations and organization were observed in these strains. Transcriptome sequencing suggests that GprM and GprJ negatively regulate genes encoding secondary metabolites (SMs). Mass spectrometry analysis confirmed that the production of fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, and fumitremorgin is reduced in the ΔgprM and ΔgprJ strains, at least partially through the activation of MpkA. Overexpression of grpM also resulted in the regulation of many transcription factors, with AsgA predicted to function downstream of GprM and MpkA signaling. Finally, we show that the ΔgprM and ΔgprJ mutants are reduced in virulence in the Galleria mellonella insect model of invasive aspergillosis. IMPORTANCE A. fumigatus is the main etiological agent of invasive pulmonary aspergillosis, a life-threatening fungal disease that occurs in severely immunocompromised humans. Withstanding the host environment is essential for A. fumigatus virulence, and sensing of extracellular cues occurs primarily through G-protein coupled receptors (GPCRs) that activate signal transduction pathways, which, in turn, regulate fungal development, metabolism, virulence, and mycotoxin biosynthesis. The A. fumigatus genome encodes 15 putative classical GPCRs, with only three having been functionally characterized to date. In this work, we show that the two GPCRs GprM and GprJ regulate the phosphorylation of the mitogen-activated protein kinase MpkA and thus control the regulation of the cell wall integrity pathway. GprM and GprJ are also involved in the regulation of the production of the secondary metabolites fumagillin, pyripyropene, fumigaclavine C, fumiquinazoline, melanin, and fumitremorgin, and this regulation partially occurs through the activation of MpkA. Furthermore, GprM and GprJ are important for virulence in the insect model Galleria mellonella. This work therefore functionally characterizes two GPCRs and shows how they regulate several intracellular pathways that have been shown to be crucial for A. fumigatus virulence.Aílton Pereira da Costa FilhoGuilherme Thomaz Pereira BranciniPatrícia Alves de CastroClara ValeroJaire Alves Ferreira FilhoLilian Pereira SilvaMarina Campos RochaIran MalavaziJoão Guilherme de Moraes PontesTaícia FillRoberto Nascimento SilvaFausto AlmeidaJacob L. SteenwykAntonis RokasThaila F. dos ReisLaure N. A. RiesGustavo H. GoldmanAmerican Society for MicrobiologyarticleAspergillus fumigatusG-protein coupled receptorcell wallsecondary metabolitesvirulenceMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)

<named-content content-type="genus-species">Aspergillus fumigatus</named-content> G-Protein Coupled Receptors GprM and GprJ Are Important for the Regulation of the Cell Wall Integrity Pathway, Secondary Metabolite Production, and Virulence

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