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A novel phosphoinositide kinase Fab1 regulates biosynthesis of pathogenic aflatoxin in Aspergillus flavus.

ABSTRACT: Aspergillus flavus (A. flavus) is one of the most important model environmental fungi which can produce a potent toxin and carcinogen known as aflatoxin. Aflatoxin contamination causes massive agricultural economic loss and a critical human health issue each year. Although a functional vacuole has been highlighted for its fundamental importance in fungal virulence, the molecular mechanisms of the vacuole in regulating the virulence of A. flavus remain largely unknown. Here, we identified a novel vacuole-related protein in A. flavus, the ortholog of phosphatidylinositol-3-phosphate-5-kinase (Fab1) in Saccharomyces cerevisiae. This kinase was located at the vacuolar membrane, and loss of fab1 function was found to affect the growth, conidia and sclerotial development, cellular acidification and metal ion homeostasis, aflatoxin production and pathogenicity of A. flavus. Further functional analysis revealed that Fab1 was required to maintain the vacuole size and cell morphology. Additional quantitative proteomic analysis suggested that Fab1 was likely to play an important role in maintaining vacuolar/cellular homeostasis, with vacuolar dysregulation upon fab1 deletion leading to impaired aflatoxin synthesis in this fungus. Together, these results provide insight into the molecular mechanisms by which this pathogen produces aflatoxin and mediates its pathogenicity, and may facilitate dissection of the vacuole-mediated regulatory network in A. flavus.

SUBMITTER: Yang M

PROVIDER: S-EPMC7781676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The Fus3-MAP kinase module is a conserved phosphorylation signal system in eukaryotes that responds to environmental stress and transduction of external signals from the outer membrane to the nucleus. Aspergillus flavus can produce aflatoxins (AF), which seriously threaten human and animal health. In this study, we determined the functions of Fus3, confirmed Ste50-Ste11-Ste7-Fus3 protein interactions and phosphorylation, and explored the possible phosphorylation motifs and potential targets of Fus3. The regulatory mechanism of Fus3 on the biosynthesis of AF was partly revealed in this study. AF production was downregulated in Δfus3, but the transcriptional expression of most AF cluster genes was upregulated. It is notable that the levels of acetyl-CoA and malonyl-CoA, the substrates of AF, were significantly decreased in fus3 defective strains. Genes involved in acetyl-CoA and malonyl-CoA biosynthesis were significantly downregulated at transcriptional or phosphorylation levels. Specifically, AccA might be a direct target of Fus3, which led to acetyl-CoA carboxylase activities were decreased in null-deletion and site mutagenesis strains. The results concluded that Fus3 could regulate the expression of acetyl-CoA and malonyl-CoA biosynthetic genes directly or indirectly, and then affect the AF production that relies on the regulation of AF substrate rather than the modulation of AF cluster genes. IMPORTANCE Aspergillus flavus is an important saprophytic fungus that produces aflatoxins (AF), which threaten food and feed safety. MAP (mitogen-activated protein) kanases are essential for fungal adaptation to diverse environments. Fus3, as the terminal kinase of a MAPK cascade, interacts with other MAPK modules and phosphorylates downstream targets. We provide evidence that Fus3 could affect AF biosynthesis by regulating the production of acetyl-CoA and malonyl-CoA, but this does not depend on the regulation of AF biosynthetic genes. Our results partly reveal the regulatory mechanism of Fus3 on AF biosynthesis and provide a novel AF modulation pattern, which may contribute to the discovery of new strategies in controlling A. flavus and AF contamination.

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A novel phosphoinositide kinase Fab1 regulates biosynthesis of pathogenic aflatoxin in Aspergillus flavus.

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