The Janus Transcription Factor HapX Controls Fungal Adaptation to Both Iron Starvation and Iron Excess

EMBO J. 2014 Oct 1;33(19):2261-76. doi: 10.15252/embj.201489468. Epub 2014 Aug 4.

Abstract

Balance of physiological levels of iron is essential for every organism. In Aspergillus fumigatus and other fungal pathogens, the transcription factor HapX mediates adaptation to iron limitation and consequently virulence by repressing iron consumption and activating iron uptake. Here, we demonstrate that HapX is also essential for iron resistance via activating vacuolar iron storage. We identified HapX protein domains that are essential for HapX functions during either iron starvation or high-iron conditions. The evolutionary conservation of these domains indicates their wide-spread role in iron sensing. We further demonstrate that a HapX homodimer and the CCAAT-binding complex (CBC) cooperatively bind an evolutionary conserved DNA motif in a target promoter. The latter reveals the mode of discrimination between general CBC and specific HapX/CBC target genes. Collectively, our study uncovers a novel regulatory mechanism mediating both iron resistance and adaptation to iron starvation by the same transcription factor complex with activating and repressing functions depending on ambient iron availability.

Keywords: fungi; iron regulation; sensing; siderophores; transcription factor complex.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological*
  • Aspergillosis / genetics
  • Aspergillosis / metabolism*
  • Aspergillosis / virology
  • Aspergillus fumigatus / pathogenicity*
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Gene Expression Regulation, Fungal*
  • Homeostasis
  • Immunoprecipitation
  • Iron / metabolism*
  • Starvation
  • Surface Plasmon Resonance
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vacuoles / metabolism
  • Virulence

Substances

  • Fungal Proteins
  • Transcription Factors
  • Iron