CircHIPK3 dysregulation of the miR-30c/DLL4 axis is essential for KSHV lytic replication
CircHIPK3 dysregulation of the miR-30c/DLL4 axis is essential for KSHV lytic replication
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DOI：
10.1101/2021.10.07.463491
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Katherine L. Harper;T. Mottram;C. Anene;Becky Foster;Molly R. Patterson;Euan Mcdonnell;A. Macdonald;D. Westhead;A. Whitehouse
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文献类型：
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作者：
Katherine L. Harper;T. Mottram;C. Anene;Becky Foster;Molly R. Patterson;Euan Mcdonnell;A. Macdonald;D. Westhead;A. Whitehouse
非编码RNA（ncRNA）调控网络正在成为基因表达的关键调控因子。这些ncRNA：ncRNA相互作用的复杂网络调节多种细胞途径并影响多种疾病的发展和进展。疱疹病毒，包括卡波西肉瘤相关疱疹病毒，擅长利用ncRNA，编码其自身以及失调宿主ncRNA，以调节病毒基因表达和宿主对感染的反应。研究主要集中在单向ncRNA介导的调节靶蛋白编码转录本，然而，我们已经确定了一个新的主机ncRNA调控网络KSHV裂解复制在B细胞中必不可少的。KSHV介导的宿主细胞circRNA（circHIPK 3）上调是该网络的关键组成部分，作为miR-30 c的竞争性内源性RNA发挥作用，导致miR-30 c靶点DLL 4水平升高。该网络的失调突出了在B细胞中KSHV裂解复制期间细胞周期控制的新机制。重要的是，在这个新的ncRNA调控网络中的任何点的中断对KSHV裂解复制具有不利影响，突出了这个网络的本质和治疗干预的潜力。
Non-coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact the development and progression of multiple diseases. Herpesviruses, including Kaposi’s sarcoma-associated herpesvirus, are adept at utilising ncRNAs, encoding their own as well as dysregulating host ncRNAs to modulate virus gene expression and the host response to infection. Research has mainly focused on unidirectional ncRNA-mediated regulation of target protein-coding transcripts; however, we have identified a novel host ncRNA regulatory network essential for KSHV lytic replication in B cells. KSHV-mediated upregulation of the host cell circRNA, circHIPK3, is a key component of this network, functioning as a competing endogenous RNA of miR-30c, leading to increased levels of the miR-30c target, DLL4. Dysregulation of this network highlights a novel mechanism of cell cycle control during KSHV lytic replication in B cells. Importantly, disruption at any point within this novel ncRNA regulatory network has a detrimental effect on KSHV lytic replication, highlighting the essential nature of this network and potential for therapeutic intervention.