The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans

PLoS Pathog. 2010 May 13;6(5):e1000889. doi: 10.1371/journal.ppat.1000889.

Abstract

Candida albicans, like other pleiomorphic fungal pathogens, is able to undergo a reversible transition between single yeast-like cells and multicellular filaments. This morphogenetic process has long been considered as a key fungal virulence factor. Here, we identify the evolutionarily conserved Set3/Hos2 histone deacetylase complex (Set3C) as a crucial repressor of the yeast-to-filament transition. Cells lacking core components of the Set3C are able to maintain all developmental phases, but are hypersusceptible to filamentation-inducing signals, because of a hyperactive cAMP/Protein Kinase A signaling pathway. Strikingly, Set3C-mediated control of filamentation is required for virulence in vivo, since set3Delta/Delta cells display strongly attenuated virulence in a mouse model of systemic infection. Importantly, the inhibition of histone deacetylase activity by trichostatin A exclusively phenocopies the absence of a functional Set3C, but not of any other histone deacetylase gene. Hence, our work supports a paradigm for manipulating morphogenesis in C. albicans through alternative antifungal therapeutic strategies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / pharmacology
  • Animals
  • Candida albicans / enzymology*
  • Candida albicans / genetics
  • Candida albicans / pathogenicity
  • Candidiasis / microbiology*
  • Carbon / metabolism
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • DNA-Binding Proteins / genetics
  • Epistasis, Genetic / physiology
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Gene Expression Regulation, Fungal / physiology
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Homozygote
  • Hyphae / drug effects
  • Hyphae / physiology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Phenotype
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Virulence

Substances

  • DNA-Binding Proteins
  • EFG1 protein, Candida albicans
  • Fungal Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Carbon
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • HOS2 protein, S cerevisiae
  • Set3 protein, S cerevisiae
  • Histone Deacetylases
  • Adenine