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<p>Iron homeostasis is key to both the survival of virtually all organisms and the virulence of fungi including <i>Aspergillus fumigatus</i>, a human fungal pathogen causing life-threatening invasive infections. Unlike the extensively studied fungal species <i>Saccharomyces cerevisiae</i> and <i>Schizosaccharomyces pombe</i>, <i>A. fumigatus</i> encodes an uncharacterized homolog of vertebrate ferroportin (Fpn1), termed FpnA. Fpn1 is the only known vertebrate iron efflux transporter, while microbial organisms are thought to lack iron efflux systems. After correcting the exon-intron annotation, inactivation and conditional overexpression of the <i>A. fumigatus</i> FpnA-encoding gene (<i>fpnA</i>) indicated, that FpnA mediates resistance to nickel, cobalt and gallium but not to iron, aluminium, cadmium, copper or zinc. Functional N-terminal tagging with a fluorescent protein demonstrated localization of FpnA in the vacuolar membrane, suggesting that FpnA detoxifies substrate metals by vacuolar deposition. In line, overexpression of <i>fpnA</i> reduced the utilization of urea as a nitrogen source, most likely by depriving cytosolic urease of its essential cofactor nickel. Phylogenetic analysis illustrated conservation of FpnA in all fungal divisions and several other eukaryotic lineages, underlining its crucial role in metal homeostasis. The divergent localization and functionalization of ferroportin homologs in two phylogenetic sister groups, metazoa and fungi, is of particular evolutionary interest.</p>

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FpnA, the Aspergillus fumigatus homolog of human ferroportin, mediates resistance to nickel, cobalt and gallium but does not function in iron homeostasis

  • 期刊论文

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  • 发表日期：

    2025年3月8日

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  • Isidor Happacher,
  • Simon Oberegger,
  • Beate Abt,
  • Annie Yap,
  • Patricia Caballero,
  • Mario Aguiar,
  • Javeria Pervaiz,
  • Giacomo Gariglio,
  • Matthias Misslinger,
  • Clemens Decristoforo,
  • Hubertus Haas

摘要

Iron homeostasis is key to both the survival of virtually all organisms and the virulence of fungi including Aspergillus fumigatus, a human fungal pathogen causing life-threatening invasive infections. Unlike the extensively studied fungal species Saccharomyces cerevisiae and Schizosaccharomyces pombe, A. fumigatus encodes an uncharacterized homolog of vertebrate ferroportin (Fpn1), termed FpnA. Fpn1 is the only known vertebrate iron efflux transporter, while microbial organisms are thought to lack iron efflux systems. After correcting the exon-intron annotation, inactivation and conditional overexpression of the A. fumigatus FpnA-encoding gene (fpnA) indicated, that FpnA mediates resistance to nickel, cobalt and gallium but not to iron, aluminium, cadmium, copper or zinc. Functional N-terminal tagging with a fluorescent protein demonstrated localization of FpnA in the vacuolar membrane, suggesting that FpnA detoxifies substrate metals by vacuolar deposition. In line, overexpression of fpnA reduced the utilization of urea as a nitrogen source, most likely by depriving cytosolic urease of its essential cofactor nickel. Phylogenetic analysis illustrated conservation of FpnA in all fungal divisions and several other eukaryotic lineages, underlining its crucial role in metal homeostasis. The divergent localization and functionalization of ferroportin homologs in two phylogenetic sister groups, metazoa and fungi, is of particular evolutionary interest.