. doi: 10.1016/j.virs.2022.09.009
Citation: Weijie Chen, Yukun Li, Xiuling Yu, Zhenwei Wang, Wenbiao Wang, Menglan Rao, Yongkui Li, Zhen Luo, Qiwei Zhang, Jinbiao Liu, Jianguo Wu. Zika virus non-structural protein 4B interacts with DHCR7 to facilitate viral infection .VIROLOGICA SINICA, 2023, 38(1) : 23-33.  http://dx.doi.org/10.1016/j.virs.2022.09.009

寨卡病毒非结构蛋白NS4B与DHCR7结合促进病毒复制

  • 寨卡病毒(ZIKV)能够利用非结构蛋白逃避免疫反应,以确保在宿主细胞中高效复制。最近有文献报道,胆固醇代谢酶7-脱氢胆固醇还原酶(DHCR7)能够影响ZIKV感染过程中的天然免疫反应。然而,ZIKV的非结构蛋白是否参与DHCR7介导的病毒逃逸尚未见报道。在本研究中,我们证实了ZIKV感染促进了DHCR7的表达。值得注意的是,上调的DHCR7反过来促进了ZIKV的感染,而阻断DHCR7抑制了ZIKV的感染。机制上,ZIKV非结构蛋白NS4B与DHCR7相互作用诱导DHCR7表达。此外,DHCR7能够抑制TANK结合激酶1(TBK1)和干扰素调节因子3(IRF3)的磷酸化,进一步降低干扰素-β(IFN-β)和干扰素刺激基因(ISGs)的表达。因此,我们提出ZIKV NS4B与DHCR7结合抑制TBK1和IRF3激活,进而抑制IFN-β和ISGs,从而促进ZIKV逃逸。本研究拓宽了对ZIKV非结构蛋白如何通过胆固醇代谢酶和中间产物抑制天然免疫促进病毒感染的认识。

Zika virus non-structural protein 4B interacts with DHCR7 to facilitate viral infection

  • Zika virus (ZIKV) evolves non-structural proteins to evade immune response and ensure efficient replication in the host cells. Cholesterol metabolic enzyme 7-dehydrocholesterol reductase (DHCR7) was recently reported to impact innate immune responses in ZIKV infection. However, the vital non-structural protein and mechanisms involved in DHCR7-mediated viral evasion are not well elucidated. In this study, we demonstrated that ZIKV infection facilitated DHCR7 expression. Notably, the upregulated DHCR7 in turn facilitated ZIKV infection and blocking DHCR7 suppressed ZIKV infection. Mechanically, ZIKV non-structural protein 4B (NS4B) interacted with DHCR7 to induce DHCR7 expression. Moreover, DHCR7 inhibited TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) phosphorylation, which resulted in the reduction of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs) productions. Therefore, we propose that ZIKV NS4B binds to DHCR7 to repress TBK1 and IRF3 activation, which in turn inhibits IFN-β and ISGs, and thereby facilitating ZIKV evasion. This study broadens the insights on how viral non-structural proteins antagonize innate immunity to facilitate viral infection via cholesterol metabolic enzymes and intermediates.

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    Zika virus non-structural protein 4B interacts with DHCR7 to facilitate viral infection

      Corresponding author: Jinbiao Liu, jinbiaoliu@jnu.edu.cn
      Corresponding author: Jianguo Wu, jwu898@jnu.edu.cn
    • a. Guangdong Provincial Key Laboratory of Virology, Institute of Medical Microbiology, Jinan University, Guangzhou, 510632, China;
    • b. Foshan Institute of Medical Microbiology, Foshan, 528315, China;
    • c. Halison International Peace Hospital, Hebei Medical University, Hengshui, 053000, China;
    • d. Medical Research Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China

    Abstract: Zika virus (ZIKV) evolves non-structural proteins to evade immune response and ensure efficient replication in the host cells. Cholesterol metabolic enzyme 7-dehydrocholesterol reductase (DHCR7) was recently reported to impact innate immune responses in ZIKV infection. However, the vital non-structural protein and mechanisms involved in DHCR7-mediated viral evasion are not well elucidated. In this study, we demonstrated that ZIKV infection facilitated DHCR7 expression. Notably, the upregulated DHCR7 in turn facilitated ZIKV infection and blocking DHCR7 suppressed ZIKV infection. Mechanically, ZIKV non-structural protein 4B (NS4B) interacted with DHCR7 to induce DHCR7 expression. Moreover, DHCR7 inhibited TANK-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) phosphorylation, which resulted in the reduction of interferon-beta (IFN-β) and interferon-stimulated genes (ISGs) productions. Therefore, we propose that ZIKV NS4B binds to DHCR7 to repress TBK1 and IRF3 activation, which in turn inhibits IFN-β and ISGs, and thereby facilitating ZIKV evasion. This study broadens the insights on how viral non-structural proteins antagonize innate immunity to facilitate viral infection via cholesterol metabolic enzymes and intermediates.

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