The Set3/Hos2 histone deacetylase complex attenuates cAMP/PKA signaling to regulate morphogenesis and virulence of Candida albicans.
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.
Hnisz
Denes
D
Medical University Vienna, Christian Doppler Laboratory for Infection Biology, Max F. Perutz Laboratories, Vienna, Austria.
Majer
Olivia
O
Frohner
Ingrid E
IE
Komnenovic
Vukoslav
V
Kuchler
Karl
K
D000225:Adenine / Q000494:pharmacology; D000818:Animals; D002176:Candida albicans / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology*; D002244:Carbon / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004843:Epistasis, Genetic / Q000502:physiology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006720:Homozygote; D025301:Hyphae / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D014774:Virulence
D004268:DNA-Binding Proteins; C121438:EFG1 protein, Candida albicans; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D002244:Carbon; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C519410:HOS2 protein, S cerevisiae; C511735:Set3 protein, S cerevisiae; D006655:Histone Deacetylases; D000225:Adenine