C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3
C19orf66 interrupts Zika virus replication by inducing lysosomal degradation of viral NS3
复制标题
C19orf66 通过诱导病毒 NS3 的溶酶体降解来中断寨卡病毒复制。
DOI：
10.1371/journal.pntd.0008083
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发表时间：
2020-03-01
影响因子：
3.8
通讯作者：
Zhu, Xun
中科院分区：
文献类型：
--
作者：
Wu, Yun;Yang, Xinyu;Zhu, Xun
ZIKV对全球健康构成严重威胁，尤其与新生儿的小头畸形和其他先天性异常以及成人的格林-巴利综合征、脑膜脑炎、多器官衰竭有关。尽管寨卡病毒感染对全球健康构成威胁，但目前还没有针对该疾病的疫苗或有效的抗病毒疗法。如广泛认识到的，干扰素信号传导是在宿主细胞中建立强抗病毒状态的关键，主要通过许多干扰素刺激基因（ISG）的抗病毒作用介导。本工作描述了我们发现的一种新的ISG C19 orf 66的抗病毒作用及其机制。我们鉴定了C19 orf 66作为一种新型ISG，其通过与ZIKV非结构（NS）蛋白NS 3特异性相互作用和共定位而发挥抗ZIKV的抗病毒作用，其通过溶酶体依赖性途径诱导NS 3降解。因此，这项工作拓宽了对C19 orf 66在宿主与ZIKV之间相互作用中的关键作用的理解，这可能进一步为开发新的抗ZIKV策略提供合理的基础。与寨卡病毒（ZIKV）流行相关的迅速出现的人类健康危机及其与严重并发症的联系突出了对确定ZIKV访问宿主的机制的日益增长的需求。干扰素反应保护宿主细胞免受病毒感染，而介导这种防御的细胞因子是干扰素刺激基因（ISG）的产物。尽管已经鉴定了数百种ISG，但只有少数ISG的抗病毒潜力、靶点特异性和作用机制得到了表征。在这项工作中，我们集中研究了新型ISG C19 orf 66响应ZIKV感染的可能抗病毒作用及其相关机制。我们发现ZIKV感染可以诱导ZIKV允许细胞中的C19 orf 66表达，并且C19 orf 66的这种过表达显著抑制ZIKV复制。相反，C19 orf 66的缺失导致病毒复制的显著增加。此外，发现C19 orf 66与ZIKV非结构蛋白3（NS 3）相互作用并共定位，从而通过溶酶体依赖性途径诱导NS 3降解。综上所述，这项研究将C19 orf 66鉴定为一种新的ISG，其通过特异性降解病毒非结构蛋白而对ZIKV发挥抗病毒作用。这些发现揭示了C19 orf 66靶向ZIKV的NS 3蛋白的有趣机制，为理解先天免疫的作用提供了线索，并提供了可用于治疗干预的新药物靶点的可能性。
Author summaryZIKV represents a serious threat to global health with particular relevance to microcephaly and other congenital abnormalities in newborns, and Guillain-Barre syndrome, meningoencephalitis, multi-organ failure in adults. Despite the global health threat of Zika virus infection, there is currently no vaccine or effective antiviral therapy available for the disease. As widely recognized, interferon signaling is key to establishing a strong antiviral state in host cells, mainly mediated through the anti-viral effects of numerous interferon-stimulated genes (ISGs). This work described our novel finding of the antiviral effect of a novel ISG, C19orf66, and its underlying mechanisms. We identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically interacting and colocalizing with the ZIKV nonstructural (NS) protein NS3, which inducing NS3 degradation via a lysosome-dependent pathway. Thus, this work broadens the understanding of the pivotal roles of C19orf66 in the interaction between the host and ZIKV, which might further provide a rational basis for developing novel anti-ZIKV strategies.The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention.