<i>Aspergillus fumigatus</i>MADS-Box Transcription Factor<i>rlmA</i>Is Required for Regulation of the Cell Wall Integrity and Virulence

Rocha, Marina Campos; Fabri, João Henrique Tadini Marilhano; Godoy, Krissia Franco de; Castro, Patrícia Alves de; Hori, Juliana Issa; Cunha, Anderson Ferreira da; Arentshorst, Mark; Ram, Arthur F. J.; Hondel, Cees A. M. J. J. van den; Goldman, Gustavo H.; Malavazi, Iran

doi:10.1534/g3.116.031112

Cited by 75 publications

(92 citation statements)

References 99 publications

(166 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To test this hypothesis, we utilized qRT-PCR to quantitate mRNA levels of transcription factors known to be induced by cell wall stress, rlmA and atfA (24, 25). We observed that the mRNA levels of both rlmA and atfA in the Δ tslA strain were equivalent to the levels seen with the wild type and the reconstituted strains with or without the presence of CFW (Fig.…”

Section: Resultsmentioning

confidence: 99%

Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity

Thammahong

Caffrey-Card

Dhingra

et al. 2017

mBio

View full text Add to dashboard Cite

Trehalose biosynthesis is found in fungi but not humans. Proteins involved in trehalose biosynthesis are essential for fungal pathogen virulence in humans and plants through multiple mechanisms. Loss of canonical trehalose biosynthesis genes in the human pathogen Aspergillus fumigatus significantly alters cell wall structure and integrity, though the mechanistic link between these virulence-associated pathways remains enigmatic. Here we characterize genes, called tslA and tslB, which encode proteins that contain domains similar to those corresponding to trehalose-6-phosphate phosphatase but lack critical catalytic residues for phosphatase activity. Loss of tslA reduces trehalose content in both conidia and mycelia, impairs cell wall integrity, and significantly alters cell wall structure. To gain mechanistic insights into the role that TslA plays in cell wall homeostasis, immunoprecipitation assays coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used to reveal a direct interaction between TslA and CsmA, a type V chitin synthase enzyme. TslA regulates not only chitin synthase activity but also CsmA sub-cellular localization. Loss of TslA impacts the immunopathogenesis of murine invasive pulmonary aspergillosis through altering cytokine production and immune cell recruitment. In conclusion, our data provide a novel model whereby proteins in the trehalose pathway play a direct role in fungal cell wall homeostasis and consequently impact fungus-host interactions.

show abstract

Section: Resultsmentioning

confidence: 99%

Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity

Thammahong

Caffrey-Card

Dhingra

et al. 2017

mBio

View full text Add to dashboard Cite

show abstract

“…In C. albicans , growth on echinocandins was shown to be strain specific (31), and strain-specific responses of different A. fumigatus clinical isolates to various caspofungin concentrations have also been observed (13). In agreement, deletion of crzA in the Af293 background strain resulted in a much more severe growth phenotype under nonstress conditions than in the CEA10 background strain (27, 32).…”

Section: Discussionmentioning

confidence: 99%

The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

Ries

Rocha

Castro

et al. 2017

mBio

Self Cite

View full text Add to dashboard Cite

Aspergillus fumigatus is an opportunistic fungal pathogen that causes invasive aspergillosis (IA), a life-threatening disease in immunocompromised humans. The echinocandin caspofungin, adopted as a second-line therapy in combating IA, is a β-1,3-glucan synthase inhibitor, which, when used in high concentrations, reverts the anticipated A. fumigatus growth inhibition, a phenomenon called the “caspofungin paradoxical effect” (CPE). The CPE has been widely associated with increased chitin content in the cell wall due to a compensatory upregulation of chitin synthase-encoding genes. Here, we demonstrate that the CPE is dependent on the cell wall integrity (CWI) mitogen-activated protein kinase MpkAMPK1 and its associated transcription factor (TF) RlmARLM1, which regulate chitin synthase gene expression in response to different concentrations of caspofungin. Furthermore, the calcium- and calcineurin-dependent TF CrzA binds to and regulates the expression of specific chitin synthase genes during the CPE. These results suggest that the regulation of cell wall biosynthetic genes occurs by several cellular signaling pathways. In addition, CrzA is also involved in cell wall organization in the absence of caspofungin. Differences in the CPE were also observed between two A. fumigatus clinical isolates, which led to the identification of a novel basic leucine zipper TF, termed ZipD. This TF functions in the calcium-calcineurin pathway and is involved in the regulation of cell wall biosynthesis genes. This study therefore unraveled additional mechanisms and novel factors governing the CPE response, which ultimately could aid in developing more effective antifungal therapies.

show abstract

“…Prior studies identified several transcription factors that are induced during sporulation in P. infestans, including the MADS-box transcription factor PiMADS (Ah- . MADS-box proteins occur in nearly all eukaryotes, where they regulate a broad spectrum of cellular processes, such as flower development (Smaczniak et al, 2012), muscle formation (Mughal et al, 2015), and fungal cell wall biosynthesis (Rocha et al, 2016). The MADSbox domain participates in DNA-binding and dimerization, and differences in the C-terminal of region of the domain have been used to classify such proteins as either type I (SRF, human serum response factor) or type II (MEF2, myocyte enhancer factor 2).…”

Section: Introductionmentioning

confidence: 99%

A MADS‐box transcription factor regulates a central step in sporulation of the oomycete Phytophthora infestans

Leesutthiphonchai

Judelson

2018

Molecular Microbiology

View full text Add to dashboard Cite

MADS-box transcription factors play significant roles in eukaryotes, but have not yet been characterized in oomycetes. Here, we describe a MADS-box protein from Phytophthora infestans, which causes late blight of potato. P. infestans and most other oomycetes express a single MADS-box gene. PiMADS is not transcribed during vegetative growth, but is induced early during asexual sporulation. Its mRNA levels oscillate in response to light, which suppresses sporulation. The protein was not detected in nonsporulating mycelia, but was found in sporulating mycelia and spores. Both mRNA and protein levels decline upon spore germination. A similar expression pattern as well as nuclear localization was observed when the protein was expressed with a fluorescent tag from the native promoter. Gene silencing triggered by a construct expressing 478 nt of MADS sequences indicated that PiMADS is required for sporulation but not hyphal growth or plant colonization. A comparison of wild type to a silenced strain by RNA-seq indicated that PiMADS regulates about 3000 sporulation-associated genes, and acts before other genes previously shown to regulate sporulation. Analysis of the silenced strain also indicated that the native gene was not transcribed while the transgene was still expressed, which contradicts current models for homology-dependent silencing in oomycetes.

show abstract

Aspergillus fumigatusMADS-Box Transcription FactorrlmAIs Required for Regulation of the Cell Wall Integrity and Virulence

Cited by 75 publications

References 99 publications

Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity

Aspergillus fumigatus Trehalose-Regulatory Subunit Homolog Moonlights To Mediate Cell Wall Homeostasis through Modulation of Chitin Synthase Activity

The Aspergillus fumigatus CrzA Transcription Factor Activates Chitin Synthase Gene Expression during the Caspofungin Paradoxical Effect

A MADS‐box transcription factor regulates a central step in sporulation of the oomycete Phytophthora infestans

Contact Info

Product

Resources

About