The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

ABSTRACT The filamentous fungus Aspergillus fumigatus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to...

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Autores principales:	Eliciane Cevolani Mattos, Lilian Pereira Silva, Clara Valero, Patrícia Alves de Castro, Thaila Fernanda dos Reis, Liliane F. C. Ribeiro, Mark R. Marten, Rafael Silva-Rocha, Cauã Westmann, Carlos Henrique Tomich de Paula da Silva, Carlton Anthony Taft, Narjes Al-Furaiji, Michael Bromley, Uffe H. Mortensen, J. Philipp Benz, Neil Andrew Brown, Gustavo H. Goldman
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Aspergillus fumigatus cell wall integrity pathway MpkC SakA caspofungin osmotic stress Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e4362aac315c465db4926930d9ce17bc
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spelling	oai:doaj.org-article:e4362aac315c465db4926930d9ce17bc2021-11-15T15:56:58ZThe <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance10.1128/mBio.02962-192150-7511https://doaj.org/article/e4362aac315c465db4926930d9ce17bc2020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02962-19https://doaj.org/toc/2150-7511ABSTRACT The filamentous fungus Aspergillus fumigatus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global A. fumigatus phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. IMPORTANCE Aspergillus fumigatus is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the ΔsakA and ΔmpkC A. fumigatus and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.Eliciane Cevolani MattosLilian Pereira SilvaClara ValeroPatrícia Alves de CastroThaila Fernanda dos ReisLiliane F. C. RibeiroMark R. MartenRafael Silva-RochaCauã WestmannCarlos Henrique Tomich de Paula da SilvaCarlton Anthony TaftNarjes Al-FuraijiMichael BromleyUffe H. MortensenJ. Philipp BenzNeil Andrew BrownGustavo H. GoldmanAmerican Society for MicrobiologyarticleAspergillus fumigatuscell wall integrity pathwayMpkCSakAcaspofunginosmotic stressMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus cell wall integrity pathway MpkC SakA caspofungin osmotic stress Microbiology QR1-502
spellingShingle	Aspergillus fumigatus cell wall integrity pathway MpkC SakA caspofungin osmotic stress Microbiology QR1-502 Eliciane Cevolani Mattos Lilian Pereira Silva Clara Valero Patrícia Alves de Castro Thaila Fernanda dos Reis Liliane F. C. Ribeiro Mark R. Marten Rafael Silva-Rocha Cauã Westmann Carlos Henrique Tomich de Paula da Silva Carlton Anthony Taft Narjes Al-Furaiji Michael Bromley Uffe H. Mortensen J. Philipp Benz Neil Andrew Brown Gustavo H. Goldman The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
description	ABSTRACT The filamentous fungus Aspergillus fumigatus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global A. fumigatus phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in ΔsakA, ΔmpkC, and ΔsakA ΔmpkC mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. IMPORTANCE Aspergillus fumigatus is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the ΔsakA and ΔmpkC A. fumigatus and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.
format	article
author	Eliciane Cevolani Mattos Lilian Pereira Silva Clara Valero Patrícia Alves de Castro Thaila Fernanda dos Reis Liliane F. C. Ribeiro Mark R. Marten Rafael Silva-Rocha Cauã Westmann Carlos Henrique Tomich de Paula da Silva Carlton Anthony Taft Narjes Al-Furaiji Michael Bromley Uffe H. Mortensen J. Philipp Benz Neil Andrew Brown Gustavo H. Goldman
author_facet	Eliciane Cevolani Mattos Lilian Pereira Silva Clara Valero Patrícia Alves de Castro Thaila Fernanda dos Reis Liliane F. C. Ribeiro Mark R. Marten Rafael Silva-Rocha Cauã Westmann Carlos Henrique Tomich de Paula da Silva Carlton Anthony Taft Narjes Al-Furaiji Michael Bromley Uffe H. Mortensen J. Philipp Benz Neil Andrew Brown Gustavo H. Goldman
author_sort	Eliciane Cevolani Mattos
title	The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
title_short	The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
title_full	The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
title_fullStr	The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
title_full_unstemmed	The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance
title_sort	<named-content content-type="genus-species">aspergillus fumigatus</named-content> phosphoproteome reveals roles of high-osmolarity glycerol mitogen-activated protein kinases in promoting cell wall damage and caspofungin tolerance
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/e4362aac315c465db4926930d9ce17bc
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The <named-content content-type="genus-species">Aspergillus fumigatus</named-content> Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance

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