Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly
Abstract Zika virus (ZIKV) is a member of the Flaviviridae family and causes congenital microcephaly and Guillain–Barré syndrome. Currently, there is a lack of approved vaccines or therapies against ZIKV infection. In this study, we profile vRNA‒host protein interactomes at ZIKV stem‒loop B (SLB) an...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56859-x |
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| author | Zhiwei Lei Yu Gu Ying Liu Hailiang Liu Xiaohua Lu Weijie Chen Lu Zhou Pan Pan Zhuohong Chen Zhaoyang Yue Jinhui Ruan Leqing Zhu Guangqiang Li Xichun Xia Yang Yu Jianfeng Dai Xin Chen |
| author_facet | Zhiwei Lei Yu Gu Ying Liu Hailiang Liu Xiaohua Lu Weijie Chen Lu Zhou Pan Pan Zhuohong Chen Zhaoyang Yue Jinhui Ruan Leqing Zhu Guangqiang Li Xichun Xia Yang Yu Jianfeng Dai Xin Chen |
| author_sort | Zhiwei Lei |
| collection | DOAJ |
| description | Abstract Zika virus (ZIKV) is a member of the Flaviviridae family and causes congenital microcephaly and Guillain–Barré syndrome. Currently, there is a lack of approved vaccines or therapies against ZIKV infection. In this study, we profile vRNA‒host protein interactomes at ZIKV stem‒loop B (SLB) and reveal that interleukin enhancer binding factor 3 (ILF3) and DEAH-box helicase 9 (DHX9) form positive regulators of antiviral RNA inference in undifferentiated human neuroblastoma cells and induced pluripotent stem cell-derived human neural stem cells (iPSC–NSCs). Functionally, ablation of ILF3 in brain organoids and Nestin-Cre ILF3 cKO foetal mice significantly enhance ZIKV replication and aggravated ZIKV-induced microcephalic phenotypes. Mechanistically, ILF3/DHX9 enhance DICER processing of ZIKV vRNA-derived siRNAs (vsiR-1 and vsiR-2) to exert anti-flavivirus activity. VsiR-1 strongly inhibits ZIKV NS5 polymerase activity and RNA translation. Treatment with the vsiR-1 mimic inhibits ZIKV replication in vitro and in vivo and protected mice from ZIKV-induced microcephaly. Overall, we propose a novel therapeutic strategy to combat flavivirus infection. |
| format | Article |
| id | doaj-art-41fba407e82f4f19b908b1edd2f4edaa |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-41fba407e82f4f19b908b1edd2f4edaa2025-08-20T03:03:50ZengNature PortfolioNature Communications2041-17232025-02-0116111810.1038/s41467-025-56859-xIdentification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephalyZhiwei Lei0Yu Gu1Ying Liu2Hailiang Liu3Xiaohua Lu4Weijie Chen5Lu Zhou6Pan Pan7Zhuohong Chen8Zhaoyang Yue9Jinhui Ruan10Leqing Zhu11Guangqiang Li12Xichun Xia13Yang Yu14Jianfeng Dai15Xin Chen16Guangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityDepartment of Medical Genetics, School of Basic Medical Sciences, Southern Medical UniversityGuangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityDepartment of Cardiology, The First Affiliated Hospital of Jinan UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityFoshan Institute of Medical MicrobiologyGuangzhou Laboratory, BiolandThe Biomedical Translational Research Institute, Faculty of Medical Science, Jinan UniversityZhuhai Institute of Translational Medicine, Zhuhai People’s Hospital Affiliated with Jinan University, Jinan UniversityGuangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityJiangsu Key Laboratory of Infection and Immunity, Institute of Biology and Medical Sciences, Soochow UniversityGuangdong Provincial Key Laboratory of Virology, Key Laboratory of Viral Pathogenesis & Infection Prevention and Control, Institute of Medical Microbiology, Jinan UniversityAbstract Zika virus (ZIKV) is a member of the Flaviviridae family and causes congenital microcephaly and Guillain–Barré syndrome. Currently, there is a lack of approved vaccines or therapies against ZIKV infection. In this study, we profile vRNA‒host protein interactomes at ZIKV stem‒loop B (SLB) and reveal that interleukin enhancer binding factor 3 (ILF3) and DEAH-box helicase 9 (DHX9) form positive regulators of antiviral RNA inference in undifferentiated human neuroblastoma cells and induced pluripotent stem cell-derived human neural stem cells (iPSC–NSCs). Functionally, ablation of ILF3 in brain organoids and Nestin-Cre ILF3 cKO foetal mice significantly enhance ZIKV replication and aggravated ZIKV-induced microcephalic phenotypes. Mechanistically, ILF3/DHX9 enhance DICER processing of ZIKV vRNA-derived siRNAs (vsiR-1 and vsiR-2) to exert anti-flavivirus activity. VsiR-1 strongly inhibits ZIKV NS5 polymerase activity and RNA translation. Treatment with the vsiR-1 mimic inhibits ZIKV replication in vitro and in vivo and protected mice from ZIKV-induced microcephaly. Overall, we propose a novel therapeutic strategy to combat flavivirus infection.https://doi.org/10.1038/s41467-025-56859-x |
| spellingShingle | Zhiwei Lei Yu Gu Ying Liu Hailiang Liu Xiaohua Lu Weijie Chen Lu Zhou Pan Pan Zhuohong Chen Zhaoyang Yue Jinhui Ruan Leqing Zhu Guangqiang Li Xichun Xia Yang Yu Jianfeng Dai Xin Chen Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly Nature Communications |
| title | Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly |
| title_full | Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly |
| title_fullStr | Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly |
| title_full_unstemmed | Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly |
| title_short | Identification of antiviral RNAi regulators, ILF3/DHX9, recruit at ZIKV stem loop B to protect against ZIKV induced microcephaly |
| title_sort | identification of antiviral rnai regulators ilf3 dhx9 recruit at zikv stem loop b to protect against zikv induced microcephaly |
| url | https://doi.org/10.1038/s41467-025-56859-x |
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