Dataset Information

The Cell Wall Integrity Signaling Pathway and Its Involvement in Secondary Metabolite Production.

ABSTRACT: The fungal cell wall is the external and first layer that fungi use to interact with the environment. Every stress signal, before being translated into an appropriate stress response, needs to overtake this layer. Many signaling pathways are involved in translating stress signals, but the cell wall integrity (CWI) signaling pathway is the one responsible for the maintenance and biosynthesis of the fungal cell wall. In fungi, the CWI signal is composed of a mitogen-activated protein kinase (MAPK) module. After the start of the phosphorylation cascade, the CWI signal induces the expression of cell-wall-related genes. However, the function of the CWI signal is not merely the activation of cell wall biosynthesis, but also the regulation of expression and production of specific molecules that are used by fungi to better compete in the environment. These molecules are normally defined as secondary metabolites or natural products. This review is focused on secondary metabolites affected by the CWI signal pathway with a special focus on relevant natural products such as melanins, mycotoxins, and antibacterial compounds.

SUBMITTER: Valiante V

PROVIDER: S-EPMC5753170 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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The Cell Wall Integrity Signaling Pathway and Its Involvement in Secondary Metabolite Production.

Valiante Vito V

Journal of fungi (Basel, Switzerland) 20171206 4

The fungal cell wall is the external and first layer that fungi use to interact with the environment. Every stress signal, before being translated into an appropriate stress response, needs to overtake this layer. Many signaling pathways are involved in translating stress signals, but the cell wall integrity (CWI) signaling pathway is the one responsible for the maintenance and biosynthesis of the fungal cell wall. In fungi, the CWI signal is composed of a mitogen-activated protein kinase (MAPK) ...[more]

PMID: 29371582

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Project description: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.

Project description:An intact cell wall is critical for cellular interactions with the environment and protecting the cell from environmental challenges. Signaling mechanisms are necessary to monitor cell wall integrity and to regulate cell wall production and remodeling during growth and division cycles. The green alga, Chlamydomonas, has a proteinaceous cell wall of defined structure that is readily removed by gametolysin (g-lysin), a metalloprotease released during sexual mating. Naked cells treated with g-lysin induce the mRNA accumulation of >100 cell wall-related genes within an hour, offering a system to study signaling and regulatory mechanisms for de novo cell wall assembly. Combining quantitative RT-PCR and luciferase reporter assays to probe transcript accumulation and promoter activity, we revealed that up to 500-fold upregulation of cell wall-related genes was driven at least partly by transcriptional activation upon g-lysin treatment. To investigate how naked cells trigger this rapid transcriptional activation, we tested whether osmotic stress and cell wall integrity are involved in this process. Under a constant hypotonic condition, comparable levels of cell wall-gene activation were observed by g-lysin treatment. In contrast, cells in an iso- or hypertonic condition showed up to 80% reduction in the g-lysin-induced gene activation, suggesting that osmotic stress is required for full-scale responses to g-lysin treatment. To test whether mechanical perturbation of cell walls is involved, we isolated and examined a new set of cell wall mutants with defective or little cell walls. All cell wall mutants examined showed a constitutive upregulation of cell wall-related genes at a level that is only achieved by treatment with g-lysin in wild-type cells. Our study suggests a cell wall integrity monitoring mechanism that senses both osmotic stress and mechanical defects of cell walls and regulates cell wall-gene expression in Chlamydomonas, which may relate to cell wall integrity signaling mechanisms in other organisms.

Dataset Information

The Cell Wall Integrity Signaling Pathway and Its Involvement in Secondary Metabolite Production.

Publications

The Cell Wall Integrity Signaling Pathway and Its Involvement in Secondary Metabolite Production.

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