Abstract:
Long non-coding RNAs (lncRNAs) represent a new group of host factors involved in viral infection. Current study identified an intergenic lncRNA, LINC08148, as a proviral factor of Zika virus (ZIKV) and Dengue virus 2 (DENV2). Knockout (KO) or silencing of LINC08148 decreases the replication of ZIKV and DENV2. LINC08148 mainly acts at the endocytosis step of ZIKV but at a later stage of DENV2. RNA-seq analysis reveals that LINC08148 knockout downregulates the transcription levels of five endocytosis-related genes including AP2B1, CHMP4C, DNM1, FCHO1, and Src. Among them, loss of Src significantly decreases the uptake of ZIKV. Trans-complementation of Src in the LINC08148KO cells largely restores the caveola-mediated endocytosis of ZIKV, indicating that the proviral effect of LINC08148 is exerted through Src. Finally, LINC08148 upregulates the Src transcription through associating with its transcription factor SP1. This work establishes an essential role of LINC08148 in the ZIKV entry, underscoring a significance of lncRNAs in the viral infection.
OBJECTIVE: Long non-coding RNAs (lncRNAs), like proteins, participate in viral infection. However, functions of most lncRNAs remain unknown. In this study, we performed a functional screen based on microarray data and identified a new proviral lncRNA, LINC08148. Then, we uncovered that LINC08148 is involved in the caveola-mediated endocytosis of ZIKV, rather than the classical clathrin-mediated endocytosis. Mechanistically, LINC08148 upregulates the transcription of Src, an initiator of caveola-mediated endocytosis, through binding to its transcription factor SP1. This study identifies a new lncRNA involved in the ZIKV infection, suggesting lncRNAs and cellular proteins are closely linked and cooperate to regulate viral infection.
摘要:
长链非编码RNA(lncRNA)代表了一组新的与病毒感染有关的宿主因子。目前的研究确定了一个基因间的lncRNA,LINC08148,作为寨卡病毒(ZIKV)和登革病毒2(DENV2)的前病毒因子。LINC08148的敲除(KO)或沉默减少ZIKV和DENV2的复制。LINC08148主要作用于ZIKV的内吞作用步骤,但作用于DENV2的后期。RNA-seq分析显示LINC08148敲除下调五个内吞相关基因的转录水平,包括AP2B1,CHMP4C,DNM1、FCHO1和Src。其中,Src的损失显著降低ZIKV的摄取。LINC08148KO细胞中Src的反式互补在很大程度上恢复了ZIKV的caveola介导的内吞作用,表明LINC08148的原作用是通过Src发挥的。最后,LINC08148通过与其转录因子SP1相关联来上调Src转录。这项工作确立了LINC08148在ZIKV条目中的重要作用,强调lncRNAs在病毒感染中的重要性。
目的:长链非编码RNA(lncRNAs),像蛋白质一样,参与病毒感染。然而,大多数lncRNAs的功能仍然未知。在这项研究中,我们基于微阵列数据进行了功能筛选,并鉴定了一种新的前病毒lncRNA,LINC08148。然后,我们发现LINC08148参与了ZIKV的caveola介导的内吞作用,而不是经典的网格蛋白介导的内吞作用。机械上,LINC08148上调Src的转录,caveola介导的内吞作用的引发者,通过与其转录因子SP1结合。本研究鉴定了一种新的参与ZIKV感染的lncRNA,这表明lncRNAs和细胞蛋白紧密相连并合作调节病毒感染。