Li Huixia, Dou Xueer, Wang Na, Lian Ruiya, Li Shasha, Xie Jingying, Li Xiangrong, Yang Yanmei, Wen Yanqiao, Feng Ruofei
Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Biomedical Research Center, Northwest Minzu University, Lanzhou 730030, China; Key Laboratory of Biotechnology and Bioengineering of State Ethnic Affairs Commission, Biomedical Research Center, Northwest Minzu University, Lanzhou 730030, China; Gansu Tech Innovation Center of Animal Cell, Biomedical Research Center, Northwest Minzu University, Lanzhou 730030, China.
Engineering Research Center of Key Technology and Industrialization of Cell-based Vaccine, Ministry of Education, Biomedical Research Center, Northwest Minzu University, Lanzhou 730030, China; College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730030, China.
Mol Immunol. 2025 Aug;184:137-148. doi: 10.1016/j.molimm.2025.06.005. Epub 2025 Jun 27.
Multiple core histones play pivotal roles in viral infection process, as evidenced in influenza virus and other viruses. Recent findings indicate that linker histone H1.2 regulates the interferon signaling pathway to modulate influenza and EMCV infections, while H1.3 may also play a role in EMCV infection. In this study, we initially demonstrated that overexpression of H1.3 markedly suppressed the EMCV replication and proliferation. Conversely, knockdown of H1.3 expression led to an upregulation of EMCV replication and proliferation. Additionally, we observed a significant enhancement of EMCV-induced type I IFN production in Myc-H1.3 expressing cells. Our further exploration revealed that H1.3 upregulated the expression of MDA5 and enhanced the phosphorylation of TBK1 and IRF3 during EMCV infection, with opposite effects observed in H1.3 knockdown cells. Subsequently, we confirmed the interaction between H1.3 and MAVS, as well as IRF3, using both endogenous and exogenous Co-IP assays. Furthermore, we demonstrated that H1.3 promoted IRF3 phosphorylation and its nuclear translocation in EMCV-infected A549 cells. Notably, the N-terminal domain of H1.3 may play a crucial role in regulating the IFN-β signaling pathway to inhibit EMCV replication. Finally, we observed that EMCV infection upregulated the phosphorylation of H1.3, which may correlate with increased transcriptional expression of genes such as IFN-β. In summary, our findings address the gap in understanding the involvement of H1.3 in viral infection and elucidate the mechanism by which H1.3 negatively regulates EMCV replication. These findings may provide new insights into potential antiviral targets.
多种核心组蛋白在病毒感染过程中发挥着关键作用，流感病毒和其他病毒的情况就是明证。最近的研究结果表明，连接组蛋白H1.2调节干扰素信号通路以调控流感病毒和脑心肌炎病毒（EMCV）感染，而H1.3可能在EMCV感染中也发挥作用。在本研究中，我们首先证明H1.3的过表达显著抑制了EMCV的复制和增殖。相反，敲低H1.3的表达导致EMCV复制和增殖上调。此外，我们观察到在表达Myc-H1.3的细胞中，EMCV诱导的I型干扰素产生显著增强。我们进一步的探索发现，在EMCV感染期间，H1.3上调了MDA5的表达，并增强了TBK1和IRF3的磷酸化，而在敲低H1.3的细胞中观察到相反的效果。随后，我们使用内源性和外源性免疫共沉淀（Co-IP）实验证实了H1.3与线粒体抗病毒信号蛋白（MAVS）以及IRF3之间的相互作用。此外，我们证明H1.3促进了EMCV感染的A549细胞中IRF3的磷酸化及其核转位。值得注意的是，H1.3的N末端结构域可能在调节IFN-β信号通路以抑制EMCV复制中起关键作用。最后，我们观察到EMCV感染上调了H1.3的磷酸化，这可能与IFN-β等基因转录表达的增加相关。总之，我们的研究结果填补了对H1.3参与病毒感染理解上的空白，并阐明了H1.3负向调控EMCV复制的机制。这些发现可能为潜在的抗病毒靶点提供新的见解。
