Mitogen-activated protein kinases MpkA and MpkB independently affect micafungin sensitivity in <i>Aspergillus nidulans</i>

Yoshimi, Akira; Fujioka, Tomonori; Mizutani, Osamu; Marui, Junichiro; Hagiwara, Daisuke; Abe, Keietsu

doi:10.1080/09168451.2014.998619

Cited by 15 publications

(10 citation statements)

References 30 publications

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“…For instance, the deletion of Candida albicans Δ/Δ RLM1 resulted in a significant increase in the chitin content and a reduction in mannans ( Delgado-Silva et al 2014 ). On the other hand, A. nidulans cell wall composition in the Δ mpkA mutant was comparable to that of the wild-type, even though the Δ mpkA mutant showed poor growth and sensitivity to micafungin ( Yoshimi et al 2015 ). These results further illustrate the point that it is critical to study the function of cell wall-related genes in fungi.…”

Section: Discussionmentioning

confidence: 98%

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

Rocha

Fabri

Godoy

et al. 2016

G3 Genes|Genomes|Genetics

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The Cell Wall Integrity (CWI) pathway is the primary signaling cascade that controls the de novo synthesis of the fungal cell wall, and in Saccharomyces cerevisiae this event is highly dependent on the RLM1 transcription factor. Here, we investigated the function of RlmA in the fungal pathogen Aspergillus fumigatus. We show that the ΔrlmA strain exhibits an altered cell wall organization in addition to defects related to vegetative growth and tolerance to cell wall-perturbing agents. A genetic analysis indicated that rlmA is positioned downstream of the pkcA and mpkA genes in the CWI pathway. As a consequence, rlmA loss-of-function leads to the altered expression of genes encoding cell wall-related proteins. RlmA positively regulates the phosphorylation of MpkA and is induced at both protein and transcriptional levels during cell wall stress. The rlmA was also involved in tolerance to oxidative damage and transcriptional regulation of genes related to oxidative stress adaptation. Moreover, the ΔrlmA strain had attenuated virulence in a neutropenic murine model of invasive pulmonary aspergillosis. Our results suggest that RlmA functions as a transcription factor in the A. fumigatus CWI pathway, acting downstream of PkcA-MpkA signaling and contributing to the virulence of this fungus.

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Section: Discussionmentioning

confidence: 98%

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

Rocha

Fabri

Godoy

et al. 2016

G3 Genes|Genomes|Genetics

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“…Real-time RT-PCR was performed as described previously (Yoshimi et al 2013 , 2015 ). Primer sets for quantifying the expression of the ustiloxin B cluster genes are listed in Additional file 1 : Table S1.…”

Section: Methodsmentioning

confidence: 99%

Expression of ustR and the Golgi protease KexB are required for ustiloxin B biosynthesis in Aspergillus oryzae

et al. 2016

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Ustiloxin B, originally isolated from the fungus Ustilaginoidea virens, is a known inhibitor of microtubule assembly. Ustiloxin B is also produced by Aspergillus flavus and is synthesized through the ribosomal peptide synthesis pathway. In A. flavus, the gene cluster associated with ustiloxin B production contains 15 genes including those encoding a fungal C6-type transcription factor and ustiloxin B precursor. Although the koji mold Aspergillus oryzae, which is genetically close to A. flavus, has the corresponding gene cluster, it does not produce ustiloxin B, which may be explained by the fact that the gene encoding the transcription factor UstR is not expressed. Here, to investigate whether ustiloxin B can be produced by expressing ustR in A. oryzae, we constructed ustR expression (ustREX) strains and analyzed ustiloxin B production. In the ustREX strains, all genes in the cluster were up-regulated, in line with expression of ustR, and ustiloxin B produced. To elucidate whether the KexB protease is involved in the processing of the ustiloxin B precursor protein UstA, which has repeats of basic amino acid doublets resembling KexB target sites, we also constructed a ustREX strain with the ∆kexB genotype. Although ustR was expressed in this strain, ustiloxin B was barely detectable. This finding strongly suggests that KexB is required for ustiloxin B production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13568-016-0181-4) contains supplementary material, which is available to authorized users.

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“…cell wall stress and increases the mRNA level of A. nidulans agsB, which is an ortholog of AGS1 of M. grisea (7,30), we treated M. grisea mycelia with MCFG and analyzed the AGS1 mRNA level by qRT-PCR. Treatment with MCFG (0.01 g/ml for 24 h) markedly upregulated the AGS1 mRNA levels ( Fig.…”

Section: And A-d)mentioning

confidence: 99%

Novel Antifungal Compound Z-705 Specifically Inhibits Protein Kinase C of Filamentous Fungi

Sugahara

Yoshimi

Shoji

et al. 2019

Appl Environ Microbiol

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The cell wall integrity signaling (CWIS) pathway is involved in fungal cell wall biogenesis. This pathway is composed of sensor proteins, protein kinase C (PKC), and the mitogen-activated protein kinase (MAPK) pathway, and it controls the transcription of many cell wall-related genes. PKC plays a pivotal role in this pathway; deficiencies in PkcA in the model filamentous fungus Aspergillus nidulans and in MgPkc1p in the rice blast fungus Magnaporthe grisea are lethal. This suggests that PKC in filamentous fungi is a potential target for antifungal agents. In the present study, to search for MgPkc1p inhibitors, we carried out in silico screening by threedimensional (3D) structural modeling and performed growth inhibition tests for M. grisea on agar plates. From approximately 800,000 candidate compounds, we selected Z-705 and evaluated its inhibitory activity against chimeric PKC expressed in Saccharomyces cerevisiae cells in which the kinase domain of native S. cerevisiae PKC was replaced with those of PKCs of filamentous fungi. Transcriptional analysis of MLP1, which encodes a downstream factor of PKC in S. cerevisiae, and phosphorylation analysis of the mitogen-activated protein kinase (MAPK) Mpk1p, which is activated downstream of PKC, revealed that Z-705 specifically inhibited PKCs of filamentous fungi. Moreover, the inhibitory activity of Z-705 was similar to that of a well-known PKC inhibitor, staurosporine. Interestingly, Z-705 inhibited melanization induced by cell wall stress in M. grisea. We discuss the relationships between PKC and melanin biosynthesis. IMPORTANCE A candidate inhibitor of filamentous fungal protein kinase C (PKC), Z-705, was identified by in silico screening. A screening system to evaluate the effects of fungal PKC inhibitors was constructed in Saccharomyces cerevisiae. Using this system, we found that Z-705 is highly selective for filamentous fungal PKC in comparison with S. cerevisiae PKC. Analysis of the AGS1 mRNA level, which is regulated by Mps1p mitogen-activated protein kinase (MAPK) via PKC, in the rice blast fungus Magnaporthe grisea revealed that Z-705 had a PKC inhibitory effect comparable to that of staurosporine. Micafungin induced hyphal melanization in M. grisea, and this melanization, which is required for pathogenicity of M. grisea, was inhibited by PKC inhibition by both Z-705 and staurosporine. The mRNA levels of 4HNR, 3HNR, and

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Mitogen-activated protein kinases MpkA and MpkB independently affect micafungin sensitivity in Aspergillus nidulans

Cited by 15 publications

References 30 publications

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

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

Expression of ustR and the Golgi protease KexB are required for ustiloxin B biosynthesis in Aspergillus oryzae

Novel Antifungal Compound Z-705 Specifically Inhibits Protein Kinase C of Filamentous Fungi

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