NS1-mediated enhancement of MVC transcription and replication promoted by KAT5/H4K12ac
NS1-mediated enhancement of MVC transcription and replication promoted by KAT5/H4K12ac
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DOI：
10.1128/jvi.01695-23
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发表时间：
2024-02-13
影响因子：
5.4
通讯作者：
Liu，Haibin
中科院分区：
文献类型：
--
作者：
Zhang，Xueyan;Guo，Jianhui;Liu，Haibin
组蛋白修饰在细胞和病毒基因表达中都起作用。然而，乙酰转移酶和组蛋白乙酰化在细小病毒感染中的作用仍然知之甚少。本研究发现组蛋白去乙酰化酶（HDAC）抑制剂trichostatin A （TSA）可促进犬细小病毒（parvovirus minute virus of canines， MVC）的复制和转录。值得注意的是，在MVC感染中，宿主乙酰转移酶KAT5、GTF3C4和KAT2A的表达增加，以及H4乙酰化（H4K12ac）的表达增加。KAT5不仅负责H4K12ac，而且对病毒复制和转录至关重要。病毒非结构蛋白NS1与KAT5相互作用，增强KAT5的表达。进一步研究表明，KAT5中的Y44可能被酪氨酸磷酸化，是ns1介导的KAT5增强和MVC高效复制所不可或缺的。数据表明，NS1与KAT5相互作用，导致H4K12ac水平增强，促进病毒复制和转录，这意味着KAT5在病毒染色质样结构中表观遗传添加H4K12ac对MVC复制至关重要。细小病毒基因组被宿主组蛋白染色化。因此，病毒需要组蛋白乙酰化和相关的乙酰转移酶来修饰组蛋白和打开密集排列的染色质结构。本研究表明，组蛋白乙酰化状态对MVC复制和转录很重要，并揭示了一种新的机制，即病毒非结构蛋白NS1劫持宿主乙酰转移酶KAT5来增强H4K12ac的组蛋白乙酰化，这依赖于KAT5中潜在的酪氨酸磷酸化位点Y44。其他细小病毒具有类似的基因组组织和编码潜力，并可能采用类似的策略进行有效的病毒复制和转录。
Histone modifications function in both cellular and viral gene expression. However, the roles of acetyltransferases and histone acetylation in parvoviral infection remain poorly understood. In the current study, we found the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), promoted the replication and transcription of parvovirus minute virus of canines (MVC). Notably, the expression of host acetyltransferases KAT5, GTF3C4, and KAT2A was increased in MVC infection, as well as H4 acetylation (H4K12ac). KAT5 is not only responsible for H4K12ac but also crucial for viral replication and transcription. The viral nonstructural protein NS1 interacted with KAT5 and enhanced its expression. Further study showed that Y44 in KAT5, which may be tyrosine-phosphorylated, is indispensable for NS1-mediated enhancement of KAT5 and efficient MVC replication. The data demonstrated that NS1 interacted with KAT5, which resulted in an enhanced H4K12ac level to promote viral replication and transcription, implying the epigenetic addition of H4K12ac in viral chromatin-like structure by KAT5 is vital for MVC replication.IMPORTANCEParvoviral genomes are chromatinized with host histones. Therefore, histone acetylation and related acetyltransferases are required for the virus to modify histones and open densely packed chromatin structures. This study illustrated that histone acetylation status is important for MVC replication and transcription and revealed a novel mechanism that the viral nonstructural protein NS1 hijacks the host acetyltransferase KAT5 to enhance histone acetylation of H4K12ac, which relies on a potential tyrosine phosphorylation site, Y44 in KAT5. Other parvoviruses share a similar genome organization and coding potential and may adapt a similar strategy for efficient viral replication and transcription.