Epigenetic Modification Is Regulated by the Interaction of Influenza A Virus Nonstructural Protein 1 with the De Novo DNA Methyltransferase DNMT3B and Subsequent Transport to the Cytoplasm for K48-Linked Polyubiquitination
Epigenetic Modification Is Regulated by the Interaction of Influenza A Virus Nonstructural Protein 1 with the De Novo DNA Methyltransferase DNMT3B and Subsequent Transport to the Cytoplasm for K48-Linked Polyubiquitination
复制标题
表观遗传修饰是通过甲型流感病毒非结构蛋白 1 与从头 DNA 甲基转移酶 DNMT3B 的相互作用以及随后转运至细胞质进行 K48 连接的多聚泛素化来调节的
DOI：
10.1128/jvi.01587-18
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发表时间：
2019-04-01
影响因子：
5.4
通讯作者：
Zhu, Ying
中科院分区：
文献类型：
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作者：
Liu, Shi;Liu, Li;Zhu, Ying
流感病毒非结构蛋白1(NS1)是一种非结构蛋白，在感染过程中发挥重要的抗干扰素作用。然而，NS1蛋白在表观遗传修饰中的明确作用尚未确定。在本研究中，NS1被发现通过抑制其启动子的DNA甲基化来调节JAK-STAT信号的一些关键调节因子的表达。此外，DNA甲基转移酶3B(Dnmt3b)负责这一过程。在研究这一事件的机制后，发现NS1与Dnmt3b相互作用，但不与DNMT3a相互作用，导致Dnmt3b从相应基因的启动子中解离。此外，NS1和Dnmt3b之间的相互作用改变了Dnmt3b从细胞核到胞浆的定位，导致K48连接的泛素化和胞浆中Dnmt3b的降解。我们的结论是，NS1与Dnmt3b相互作用并改变其定位，以介导K48连锁的多泛素化，随后有助于调节JAK-STAT信号抑制物的表达。重要的是，甲型流感病毒(IAV)的非结构蛋白1(NS1)是一种多功能蛋白，具有抗细胞抗病毒活性，是一个毒力因子。然而，NS1在IAV感染过程中参与DNA甲基化的研究尚未确定。在这里，我们揭示了NS1蛋白与细胞Dnmt3b DNA甲基转移酶结合，从而抑制了JAK-STAT信号抑制物基因启动子的甲基化。结果，这些抑制基因被诱导，JAK-STAT信号被抑制。此外，我们还证明了NS1蛋白将Dnmt3b转运到细胞质中进行泛素化和降解。因此，我们确定NS1蛋白是JAK-STAT信号抑制因子表观遗传去调控的潜在触发因素，并阐明了IAV感染过程中宿主免疫调节的新机制。
The influenza virus nonstructural protein 1 (NS1) is a nonstructural protein that plays a major role in antagonizing host interferon responses during infection. However, a clear role for the NS1 protein in epigenetic modification has not been established. In this study, NS1 was found to regulate the expression of some key regulators of JAK-STAT signaling by inhibiting the DNA methylation of their promoters. Furthermore, DNA methyltransferase 3B (DNMT3B) is responsible for this process. Upon investigating the mechanisms underlying this event, NS1 was found to interact with DNMT3B but not DNMT3A, leading to the dissociation of DNMT3B from the promoters of the corresponding genes. In addition, the interaction between NS1 and DNMT3B changed the localization of DNMT3B from the nucleus to the cytosol, resulting in K48-linked ubiquitination and degradation of DNMT3B in the cytosol. We conclude that NS1 interacts with DNMT3B and changes its localization to mediate K48-linked polyubiquitination, subsequently contributing to the modulation of the expression of JAK-STAT signaling suppressors.IMPORTANCE The nonstructural protein 1 (NS1) of the influenza A virus (IAV) is a multifunctional protein that counters cellular antiviral activities and is a virulence factor. However, the involvement of NS1 in DNA methylation during IAV infection has not been established. Here, we reveal that the NS1 protein binds the cellular DNMT3B DNA methyltransferase, thereby inhibiting the methylation of the promoters of genes encoding suppressors of JAK-STAT signaling. As a result, these suppressor genes are induced, and JAK-STAT signaling is inhibited. Furthermore, we demonstrate that the NS1 protein transports DNMT3B to the cytoplasm for ubiquitination and degradation. Thus, we identify the NS1 protein as a potential trigger of the epigenetic deregulation of JAK-STAT signaling suppressors and illustrate a novel mechanism underlying the regulation of host immunity during IAV infection.