Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis.
Candida albicans is a ubiquitous opportunistic pathogen that is the most prevalent cause of hospital-acquired fungal infections. In mammalian hosts, C. albicans is engulfed by phagocytes that attack the pathogen with DNA-damaging reactive oxygen species (ROS). Acetylation of histone H3 lysine 56 (H3K56) by the fungal-specific histone acetyltransferase Rtt109 is important for yeast model organisms to survive DNA damage and maintain genome integrity. To assess the importance of Rtt109 for C. albicans pathogenicity, we deleted the predicted homolog of Rtt109 in the clinical C. albicans isolate, SC5314. C. albicans rtt109(-/-) mutant cells lack acetylated H3K56 (H3K56ac) and are hypersensitive to genotoxic agents. Additionally, rtt109(-/-) mutant cells constitutively display increased H2A S129 phosphorylation and elevated DNA repair gene expression, consistent with endogenous DNA damage. Importantly, C. albicans rtt109(-/-) cells are significantly less pathogenic in mice and more susceptible to killing by macrophages in vitro than are wild-type cells. Via pharmacological inhibition of the host NADPH oxidase enzyme, we show that the increased sensitivity of rtt109(-/-) cells to macrophages depends on the host's ability to generate ROS, providing a mechanistic link between the drug sensitivity, gene expression, and pathogenesis phenotypes. We conclude that Rtt109 is particularly important for fungal pathogenicity, suggesting a unique target for therapeutic antifungal compounds.
Lopes da Rosa
Jessica
J
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605-2324, USA.
Boyartchuk
Victor L
VL
Zhu
Lihua Julie
LJ
Kaufman
Paul D
PD
D000818:Animals; D002176:Candida albicans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity; D002177:Candidiasis / Q000382:microbiology*; D002470:Cell Survival; D004260:DNA Repair; D004271:DNA, Fungal / Q000235:genetics / Q000378:metabolism; D005260:Female; D015966:Gene Expression Regulation, Fungal; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017382:Reactive Oxygen Species / Q000378:metabolism
D004271:DNA, Fungal; D017382:Reactive Oxygen Species; D051548:Histone Acetyltransferases