Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis
Histone acetyltransferase Rtt109 is required for Candida albicans pathogenesis
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DOI：
10.1073/pnas.0912427107
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发表时间：
2010-01-26
影响因子：
11.1
通讯作者：
Kaufman, Paul D.
中科院分区：
文献类型：
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作者：
da Rosa, Jessica Lopes;Boyartchuk, Victor L.;Kaufman, Paul D.
白色念珠菌是一种普遍存在的机会性病原体，是医院获得性真菌感染的最常见原因。在哺乳动物宿主中，白色念珠菌被吞噬细胞吞噬，吞噬细胞用损伤 DNA 的活性氧 (ROS) 攻击病原体。真菌特异性组蛋白乙酰转移酶 Rtt109 对组蛋白 H3 赖氨酸 56 (H3K56) 的乙酰化对于酵母模型生物在 DNA 损伤中存活并维持基因组完整性非常重要。为了评估 Rtt109 对白色念珠菌致病性的重要性，我们删除了临床白色念珠菌分离株 SC5314 中预测的 Rtt109 同源物。白色念珠菌 rtt109(-/-) 突变细胞缺乏乙酰化 H3K56 (H3K56ac)，并且对基因毒性剂过敏。此外，rtt109(-/-)突变细胞组成性地表现出H2A S129磷酸化增加和DNA修复基因表达增加，这与内源性DNA损伤一致。重要的是，与野生型细胞相比，白色念珠菌 rtt109(-/-) 细胞在小鼠中的致病性明显较低，并且在体外更容易被巨噬细胞杀死。通过对宿主 NADPH 氧化酶的药理抑制，我们发现 rtt109(-/-) 细胞对巨噬细胞的敏感性增加取决于宿主产生 ROS 的能力，从而在药物敏感性、基因表达和发病机制表型之间提供了机制联系。我们得出结论，Rtt109 对于真菌致病性特别重要，表明治疗性抗真菌化合物的独特靶点。
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.