title: Ybp1 and Gpx3 signaling in Candida albicans govern hydrogen peroxide-induced oxidation of the Cap1 transcription factor and macrophage escape.
abstract: OBJECTIVE
  As Candida albicans is the major fungal pathogen of humans, there is an urgent need to understand how this pathogen evades toxic reactive oxygen species (ROS) generated by the host immune system. A key regulator of antioxidant gene expression, and thus ROS resistance, in C. albicans is the AP-1-like transcription factor Cap1. Despite this, little is known regarding the intracellular signaling mechanisms that underlie the oxidation and activation of Cap1. Therefore, the aims of this study were; (i) to identify the regulatory proteins that govern Cap1 oxidation, and (ii) to investigate the importance of Cap1 oxidation in C. albicans pathogenesis.
  
  
  RESULTS
  In response to hydrogen peroxide (H2O2), but not glutathione-depleting/modifying oxidants, Cap1 oxidation, nuclear accumulation, phosphorylation, and Cap1-dependent gene expression, is mediated by a glutathione peroxidase-like enzyme, which we name Gpx3, and an orthologue of the Saccharomyces cerevisiae Yap1 binding protein, Ybp1. In addition, Ybp1 also functions to stabilise Cap1 and this novel function is conserved in S. cerevisiae. C. albicans cells lacking Cap1, Ybp1, or Gpx3, are unable to filament and thus, escape from murine macrophages after phagocytosis, and also display defective virulence in the Galleria mellonella infection model.
  
  
  METHODS
  Ybp1 is required to promote the stability of fungal AP-1-like transcription factors, and Ybp1 and Gpx3 mediated Cap1-dependent oxidative stress responses are essential for the effective killing of macrophages by C. albicans.
  
  
  CONCLUSIONS
  Activation of Cap1, specifically by H2O2, is a prerequisite for the subsequent filamentation and escape of this fungal pathogen from the macrophage.
authors.affiliation: 1 Faculty of Medical Sciences, Institute for Cell and Molecular Biosciences, Newcastle University , Newcastle upon Tyne, United Kingdom .
authors.forename: Miranda J
authors.initials: MJ
authors.lastname: Patterson
authors.forename: Christopher G
authors.initials: CG
authors.lastname: McKenzie
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Smith
authors.forename: Alessandra
authors.initials: A
authors.lastname: da Silva Dantas
authors.forename: Sam
authors.initials: S
authors.lastname: Sherston
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Veal
authors.forename: Brian A
authors.initials: BA
authors.lastname: Morgan
authors.forename: Donna M
authors.initials: DM
authors.lastname: MacCallum
authors.forename: Lars-Peter
authors.initials: LP
authors.lastname: Erwig
authors.forename: Janet
authors.initials: J
authors.lastname: Quinn
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism*; D002176:Candida albicans / Q000187:drug effects / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D010084:Oxidation-Reduction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C426523:CAP1 protein, Candida albicans; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D006861:Hydrogen Peroxide