In eukaryotes, histone acetylation catalyzed by histone acetyltransferase (HAT) has been demonstrated to be critical for various physiological processes. However, the biological functions of HAT and the underlying mechanism by which HAT-regulated processes are involved in fungal development and virulence in the human opportunistic pathogen Aspergillus fumigatus remain largely unexplored. Here, we functionally characterized the roles of Rtt109 in A. fumigatus, an ortholog of Saccharomyces cerevisiae histone acetyltransferase Rtt109. In vivo and in vitro HAT assays revealed that AfRtt109 functions as a canonical histone acetyltransferase, acetylating lysines 9 and 56 of histone H3. Deletion of Afrtt109 leads to severe defects in vegetative growth, conidiation, and causes reduced virulence in the Galleria mellonella model, as well as hypersensitivity to genotoxic agents. Moreover, site-directed mutagenesis revealed that the conserved arginine residues R265 and R306 of Rtt109 are required for the H3K9 and H3K56 acetylation and virulence of A. fumigatus. Unexpectedly, R265E and R306E mutants did not exhibit any detectable phenotypic defects, implying that A. fumigatus Rtt109 regulates fungal development via histone acetylation-independent mechanisms. Together, our results revealed the critical role of fungal-specific HAT Rtt109 in regulating fungal development and virulence, and suggested that it may serve as a unique target for antifungal therapies.

中文翻译：

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真菌特异性组蛋白乙酰转移酶 Rtt109 调节烟曲霉的发育、DNA 损伤反应和毒力

在真核生物中，组蛋白乙酰转移酶 (HAT) 催化的组蛋白乙酰化已被证明对各种生理过程至关重要。然而，HAT 的生物学功能以及 HAT 调节的过程参与人类机会性病原体烟曲霉的真菌发育和毒力的潜在机制在很大程度上仍未得到探索。在这里，我们在功能上表征了 Rtt109 在A 中的作用。fumigatus，酿酒酵母组蛋白乙酰转移酶 Rtt109的直向同源物。体内和体外 HAT 测定表明，Af Rtt109 作为典型的组蛋白乙酰转移酶，乙酰化组蛋白 H3 的第 9 位和第 56 位赖氨酸。删除Afrtt109导致营养生长、分生孢子形成的严重缺陷，并导致大蜡螟模型的毒力降低，以及对基因毒性剂的超敏反应。此外，定点诱变显示 Rtt109 的保守精氨酸残基 R265 和 R306 是 A 的 H3K9 和 H3K56 乙酰化和毒力所必需的。熏蒸。出乎意料的是，R265E 和 R306E 突变体没有表现出任何可检测的表型缺陷，这意味着A . 熏烟Rtt109 通过不依赖组蛋白乙酰化的机制调节真菌发育。总之，我们的结果揭示了真菌特异性 HAT Rtt109 在调节真菌发育和毒力方面的关键作用，并表明它可以作为抗真菌治疗的独特靶点。