A fungal ABC transporter FgAtm1 regulates iron homeostasis via the transcription factor cascade FgAreA-HapX

Iron homeostasis is important for growth, reproduction and other metabolic processes in all eukaryotes. However, the functions of ATP-binding cassette (ABC) transporters in iron homeostasis are largely unknown. Here, we found that one ABC transporter (named FgAtm1) is involved in regulating iron homeostasis, by screening sensitivity to iron stress for 60 ABC transporter mutants of Fusarium graminearum, a devastating fungal pathogen of small grain cereal crops worldwide. The lack of FgAtm1 reduces the activity of cytosolic Fe-S proteins nitrite reductase and xanthine dehydrogenase, which causes high expression of FgHapX via activating transcription factor FgAreA. FgHapX represses transcription of genes for iron-consuming proteins directly but activates genes for iron acquisition proteins by suppressing another iron regulator FgSreA. In addition, the transcriptional activity of FgHapX is regulated by the monothiol glutaredoxin FgGrx4. Furthermore, the phosphorylation of FgHapX, mediated by the Ser/Thr kinase FgYak1, is required for its functions in iron homeostasis. Taken together, this study uncovers a novel regulatory mechanism of iron homeostasis mediated by an ABC transporter in an important pathogenic fungus. Author summary Essential element iron plays important roles in many cellular processes in all organisms. The function of an ATP-binding cassette (ABC) transporter Atm1 in iron homeostasis has been characterized in Saccharomyces cerevisiae. Our study found that FgAtm1 regulates iron homeostasis via the transcription factor cascade FgAreA-HapX in F. graminearum and the function of FgHapX is dependent on its interaction with FgGrx4 and phosphorylation by the Ser/Thr kinase FgYak1. This study reveals a novel regulatory mechanism of iron homeostasis in an important plant pathogenic fungus, and advances our understanding in iron homeostasis and functions of ABC transporters in eukaryotes.