Infection-Induced Retrotransposon-Derived Noncoding RNAs Enhance Herpesviral Gene Expression via the NF-κB Pathway.
Infection-Induced Retrotransposon-Derived Noncoding RNAs Enhance Herpesviral Gene Expression via the NF-κB Pathway.
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DOI：
10.1371/journal.ppat.1005260
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发表时间：
2015
期刊：
影响因子：
6.7
通讯作者：
Glaunsinger BA
中科院分区：
文献类型：
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作者：
Karijolich J;Abernathy E;Glaunsinger BA
短散在核元件（西内斯）是高度丰富的RNA聚合酶III转录的非编码逆转录转座子，其在体细胞中沉默，但在包括病毒感染在内的某些胁迫期间被激活。这些诱导的SINE RNA如何影响宿主-病原体相互作用尚不清楚。我们发现在小鼠γ疱疹病毒68（MHV 68）感染过程中，快速诱导的SINE RNA通过线粒体抗病毒信号蛋白（MAVS）依赖性和非依赖性机制激活抗病毒NF-κB信号通路。然而，基于SINE RNA的信号传导被病毒劫持以增强病毒基因表达和复制。B2 RNA表达刺激IKKβ依赖性磷酸化主要病毒裂解周期反式激活蛋白RTA，从而增强其活性并增加子代病毒体产生。总的来说，这些发现表明，SINE RNA参与先天性病原体反应机制，但疱疹病毒已经进化到协同逆转录转座子激活病毒的好处。短散在核元件（Short interspersed nuclear elements，西内斯）是一种非编码的移动的遗传元件，每个哺乳动物基因组约有106个拷贝，约占哺乳动物基因组真实的结构的10%。西内斯通常是转录沉默的，尽管在某些情况下病毒感染可以促进其表达，但功能结果未知。因此，SINE元件代表了最大的一类感染诱导型非编码RNA，其功能未被表征。在这里，我们揭示了SINE RNA在宿主-病原体相互作用中起着关键作用，因为它们是有效的鼠γ疱疹病毒68（MHV 68）复制和基因表达所必需的。我们证明了外源表达和感染诱导的SINE RNA都是IKKβ激酶的强大激活剂，IKKβ激酶是先天免疫应答中的关键信号分子。SINE RNA对IKKβ激酶的激活通过MAVS依赖性和非依赖性机制介导。此外，我们证明了IKKβ通过SINE RNA的激活是驱动MHV 68 RTA磷酸化所必需的，MHV 68 RTA是主要的病毒转录激活因子，这增强了其转录激活特性。总的来说，我们揭示了SINE RNA在宿主-病原体相互作用中的作用的第一个例子，并将其确定为感染早期的关键免疫信号分子。虽然SINE RNA激活先天免疫应答，但MHV 68已经选择SINE介导的先天免疫激活来增强病毒生命周期。
Short interspersed nuclear elements (SINEs) are highly abundant, RNA polymerase III-transcribed noncoding retrotransposons that are silenced in somatic cells but activated during certain stresses including viral infection. How these induced SINE RNAs impact the host-pathogen interaction is unknown. Here we reveal that during murine gammaherpesvirus 68 (MHV68) infection, rapidly induced SINE RNAs activate the antiviral NF-κB signaling pathway through both mitochondrial antiviral-signaling protein (MAVS)-dependent and independent mechanisms. However, SINE RNA-based signaling is hijacked by the virus to enhance viral gene expression and replication. B2 RNA expression stimulates IKKβ-dependent phosphorylation of the major viral lytic cycle transactivator protein RTA, thereby enhancing its activity and increasing progeny virion production. Collectively, these findings suggest that SINE RNAs participate in the innate pathogen response mechanism, but that herpesviruses have evolved to co-opt retrotransposon activation for viral benefit. Short interspersed nuclear elements (SINEs) are noncoding mobile genetic elements that are present at ~106 copies per mammalian genome, roughly comprising 10% of mammalian genomic real estate. SINEs are typically transcriptionally silenced, though in some cases viral infection can promote their expression, yet to an unknown functional outcome. Thus, SINE elements represent the largest class of infection-inducible noncoding RNAs that are functionally uncharacterized. Here, we reveal that SINE RNAs play a critical role in the host-pathogen interaction in that they are required for efficient murine gammaherpesvirus 68 (MHV68) replication and gene expression. We demonstrate that SINE RNAs, both exogenously expressed and infection-induced, are robust activators of the IKKβ kinase, a key signaling molecule in the innate immune response. Activation of the IKKβ kinase by SINE RNA is mediated through both MAVS-dependent and independent mechanisms. Moreover, we demonstrate the activation of the IKKβ via SINE RNA is required to drive the phosphorylation of MHV68 RTA, the main viral transcriptional activator, which enhances its transcriptional activating property. Collectively, we reveal the first example of a role for SINE RNAs in the host-pathogen interaction and identify them as a key immune signaling molecule early during infection. Though SINE RNAs activate the innate immune response, MHV68 has co-opted SINE-mediate innate immune activation to enhance the viral lifecycle.