Abstract
SAGA (Spt-Ada-Gcn5-acetyltransferase) is a highly conserved, multiprotein co-activator complex that consists of five distinct modules. It has two enzymatic functions, a histone acetyltransferase (HAT) and a deubiquitinase (DUB) and plays a central role in processes such as transcription initiation, elongation, protein stability, and telomere maintenance. We analyzed conditional and null mutants of the SAGA complex module components in the fungal pathogen Candida albicans; Ngg1, (the HAT module); Ubp8, (the DUB module); Tra1, (the recruitment module), Spt7, (the architecture module) and Spt8, (the TBP interaction unit), and assessed their roles in a variety of cellular processes. We observed that spt7Δ/Δ and spt8Δ/Δ strains have a filamentous phenotype, and both are highly invasive in yeast growing conditions as compared to the wild type, while ngg1Δ/Δ and ubp8Δ/Δ are in yeast-locked state and non-invasive in both YPD media and filamentous induced conditions compared to wild type. RNA-sequencing-based transcriptional profiling of SAGA mutants reveals upregulation of hyphal specific genes in spt7Δ/Δ and spt8Δ/Δ strains and downregulation of ergosterol metabolism pathway. As well, spt7Δ/Δ and spt8Δ/Δ confer susceptibility to antifungal drugs, to acidic and alkaline pH, to high temperature, and to osmotic, oxidative, cell wall, and DNA damage stresses, indicating that these proteins are important for genotoxic and cellular stress responses. Despite having similar morphological phenotypes (constitutively filamentous and invasive) spt7 and spt8 mutants displayed variation in nuclear distribution where spt7Δ/Δ cells were frequently binucleate and spt8Δ/Δ cells were consistently mononucleate. We also observed that spt7Δ/Δ and spt8Δ/Δ mutants were quickly engulfed by macrophages compared to ngg1Δ/Δ and ubp8Δ/Δ strains. All these findings suggest that the SAGA complex modules can have contrasting functions where loss of Spt7 or Spt8 enhances filamentation and invasiveness while loss of Ngg1 or Ubp8 blocks these processes.
Highlights
Candida albicans is a widely distributed fungus and an important cause of hospital-acquired infections (Nobile and Johnson, 2015)
This would suggest that Tra1 is an essential protein in the SAGA complex, as previously found by in vivo transposon mutagenesis and machine learning analysis in a stable haploid isolate of C. albicans (Segal et al, 2018); but because of the complexity introduced by the GRACE strain phenotype this point needs further confirmation
We have provided an overview of different components of SAGA complex regulating growth, morphogenesis, invasiveness, biofilm formation and response to environmental stresses in C. albicans (Table 3)
Summary
Candida albicans is a widely distributed fungus and an important cause of hospital-acquired infections (Nobile and Johnson, 2015). When anatomical barriers are damaged due to changes in nutritional state, prolonged antibiotic use, diseases, or immunosuppressant therapy, these conditions can result in Candida overgrowth (Calderone and Fonzi, 2001) Overall, such C. albicans infections vary from superficial mucosal growth to life threatening systemic infections. The switching of C. albicans to different morphological states is closely associated with pathogenesis and biofilm formation (Jabra-Rizk etal., 2004; Ramage et al, 2005; Calderone and Clancy, 2012; Chauvel et al, 2012). This pathogen can form dense biofilms on various biomaterials that are resistant to antifungal agents (Kojic and Darouiche, 2004). Despite the widespread studies undertaken in C. albicans, we still lack a clear, comprehensive understanding of the complexity of cellular functions and transcriptional regulation of this opportunistic fungus
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