Linker histone H1.3 promotes IFN-β production targeting MDA5 signaling to inhibit EMCV infection

Huixia Li; Xueer Dou; Na Wang; Ruiya Lian; Shasha Li; Jingying Xie; Xiangrong Li; Yanmei Yang; Yanqiao Wen; Ruofei Feng

doi:10.1016/j.molimm.2025.06.005

Linker histone H1.3 promotes IFN-β production targeting MDA5 signaling to inhibit EMCV infection

Mol Immunol. 2025 Jun 27:184:137-148. doi: 10.1016/j.molimm.2025.06.005. Online ahead of print.

Authors

Huixia Li¹, Xueer Dou¹, Na Wang¹, Ruiya Lian², Shasha Li³, Jingying Xie³, Xiangrong Li¹, Yanmei Yang², Yanqiao Wen², Ruofei Feng⁴

Affiliations

¹ 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.
² 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.
³ 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; College of Life Science and Engineering, Northwest Minzu University, Lanzhou 730030, China.
⁴ 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. Electronic address: fengruofei@xbmu.edu.cn.

PMID: 40580683
DOI: 10.1016/j.molimm.2025.06.005

Abstract

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.

Keywords: Encephalomyocarditis virus; IRF3; Interferon; Linker histone H1.3; MDA5.