组蛋白修饰在细胞和病毒基因表达中起作用。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。在目前的研究中,我们发现了组蛋白去乙酰化酶(HDAC)抑制剂,曲古霉素A(TSA),促进犬细小病毒微小病毒(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)。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相互作用并增强其表达。进一步的研究表明,KAT5中的Y44可能是酪氨酸磷酸化的,对于NS1介导的KAT5增强和有效的MVC复制是必不可少的。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,通过KAT5在病毒染色质样结构中表观遗传添加H4K12ac对于MVC复制至关重要。重要细小病毒基因组用宿主组蛋白进行层析。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开放密集的染色质结构。这项研究表明,组蛋白乙酰化状态对MVC复制和转录很重要,并揭示了病毒非结构蛋白NS1劫持宿主乙酰转移酶KAT5以增强H4K12ac的组蛋白乙酰化的新机制,依赖于潜在的酪氨酸磷酸化位点,Y44在KAT5。其他细小病毒具有相似的基因组组织和编码潜力,并且可以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.