The fungal-specific histone acetyltransferase Rtt109 regulates development, DNA damage response, and virulence in Aspergillus fumigatus
The fungal-specific histone acetyltransferase Rtt109 regulates development, DNA damage response, and virulence in Aspergillus fumigatus
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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
DOI：
10.1111/mmi.14665
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发表时间：
2021
影响因子：
3.6
通讯作者：
Lu Ling
中科院分区：
文献类型：
--
作者：
Zhang Yuanwei;Fan Jialu;Ye Jing;Lu Ling
在真核生物中，由组蛋白乙酰转移酶（histone acetyltransferase， HAT）催化的组蛋白乙酰化已被证明对多种生理过程至关重要。然而，HAT的生物学功能以及HAT调控过程参与人类机会致病菌烟曲霉真菌发育和毒力的潜在机制在很大程度上仍未被探索。在这里，我们对Rtt109 inA的作用进行了功能表征。酿酒酵母组蛋白乙酰转移酶Rtt109的同源物。体内和体外HAT实验显示，afrtt109作为一种典型的组蛋白乙酰转移酶，使组蛋白H3的赖氨酸9和56乙酰化。afrtt109的缺失会导致营养生长和条件发育的严重缺陷，并导致mellonellia模型的毒力降低，以及对遗传毒性药物的过敏。此外，位点定向诱变表明，Rtt109的保守精氨酸残基R265和R306是烟曲霉H3K9和H3K56乙酰化和毒力所必需的。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。fumigatusRtt109通过不依赖于组蛋白乙酰化的机制调节真菌的发育。总之，我们的研究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，并表明它可能作为抗真菌治疗的独特靶点。
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 pathogenAspergillus fumigatusremain largely unexplored. Here, we functionally characterized the roles of Rtt109 inA.fumigatus, an ortholog ofSaccharomyces cerevisiaehistone acetyltransferase Rtt109. In vivo and in vitro HAT assays revealed thatAfRtt109 functions as a canonical histone acetyltransferase, acetylating lysines 9 and 56 of histone H3. Deletion ofAfrtt109leads to severe defects in vegetative growth, conidiation, and causes reduced virulence in theGalleria mellonellamodel, 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 ofA.fumigatus. Unexpectedly, R265E and R306E mutants did not exhibit any detectable phenotypic defects, implying thatA.fumigatusRtt109 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.