The Set3/Hos2 Histone Deacetylase Complex Attenuates cAMP/PKA Signaling to Regulate Morphogenesis and Virulence of Candida albicans

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 set3Δ/Δ 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.

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

“…Recently, the Set3/Hos2 histone deacetylase complex (HDAC) was implicated as a regulator of C. albicans morphogenesis by acting upstream of Efg1 to repress cAMP-PKA signaling (226). The homozygous deletion of HOS2 or SET3 leads to extensive filamentation at 37°C on solid rich medium (226).…”

“…The homozygous deletion of HOS2 or SET3 leads to extensive filamentation at 37°C on solid rich medium (226). Furthermore, set3 or hos2 mutants have elevated expression levels of Efg1-dependent target genes, including HWP1 (226).…”

“…Furthermore, set3 or hos2 mutants have elevated expression levels of Efg1-dependent target genes, including HWP1 (226). Notably, set3 mutants have attenuated virulence in a murine infection model (226).…”

Functional characterization of Candida albicans Hos2 histone deacetylase

“…Hos2/Set3 histone deacetylase complex (Set3C) plays a key role in the conversion of white phase to virulent opaque phase in C. albicans 21 . Deletion of Hos2, the catalytic subunit of the Set3 complex produced a phenotype resembling inhibition of the Set3C by Trichostatin-A (TSA) 22 . Serum-induced morphogenesis of some C. albicans strains was shown to be inhibited by TSA 19 .…”

Histone deacetylases: Targets for antifungal drug development

“…Gene inactivation experiments led to association of individual HDAC genes with morphological transitions, virulence and expression and regulation of important drug resistance associated proteins, as the chaperone Hsp90 protein and drug efflux pumps. [8][9][10][11] Interestingly, inactivation of C. albicans HDAC coding genes HDA1 and RPD3 led to reduced trailing growth and reduced capability to evolve azole resistance, possibly due to a effect of these HDACs on the expression regulation of efflux pumps. 12 In the pathogenic mold Aspergillus fumigatus, HDAC gene inactivation led to defects in germination and in secondary metabolite production.…”