State Key Laboratory of Genetic Engineering & MOE Key Laboratory of Contemporary Anthropology, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, School of Life Sciences and Huashan Hospital, Fudan University, Shanghai, People's Republic of China.
Ministry of Education Key Laboratory of Contemporary Anthropology, Human Phenome Institute, School of Life Sciences, Fudan University, Shanghai, People's Republic of China.
mBio. 2019 Jul 30;10(4):e00937-19. doi: 10.1128/mBio.00937-19.
Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this "enemy within" may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses. Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.
内源性逆转录病毒（ERVs）是转座元件，可导致宿主基因组不稳定，通常在肿瘤发生等疾病中发挥有害作用。最近的进展还表明，这种“内部敌人”可能编码一种病毒模拟物，通过病毒传感器诱导抗病毒免疫反应。在这里，我们通过 RNA 测序（RNA-Seq）进行全基因组转录组分析，发现全长 ERV 衍生的长非编码 RNA（lncRNA），命名为 lnc-EPAV（ERV 衍生的长非编码 RNA 正向调节抗病毒反应），是 NF-κB 信号的正调节剂。lnc-EPAV 的表达被病毒 RNA 模拟物或 RNA 病毒迅速上调，以促进 RELA 的表达，RELA 是抗病毒反应中起关键作用的 NF-κB 亚基。lnc-EPAV 沉默的巨噬细胞的转录组分析表明，lnc-EPAV 对 RELA 靶基因表达和固有免疫反应至关重要。一致地，lnc-EPAV 缺陷小鼠在致死性 RNA 病毒感染后表现出 I 型干扰素（IFN）表达降低，因此病毒载量和死亡率增加。在机制上，lnc-EPAV 通过竞争性结合和置换转录抑制因子 SFPQ 来促进 RELA 的表达。总之，我们的工作证明了 ERV 通过竞争结合和置换转录抑制因子 SFPQ 来促进 RELA 的表达。
内源性逆转录病毒是包含人类和小鼠基因组 8%至 10%的可移动遗传元件。尽管大多数 ERV 由于有害突变而失活，但有些仍在转录。然而，转录的 ERV 的生物学功能在很大程度上是未知的。在这里，我们鉴定了全长 ERV 衍生的 lncRNA，命名为 lnc-EPAV，作为宿主固有免疫反应的正调节剂。我们发现沉默 lnc-EPAV 会损害病毒诱导的细胞因子产生，从而导致病毒复制增加。lnc-EPAV 缺陷小鼠对病毒攻击的易感性增加。我们还发现 lnc-EPAV 调节 RELA 的表达，RELA 是抗病毒反应中起关键作用的 NF-κB 亚基。ERV 衍生的 lncRNA 与转录抑制因子 SFPQ 协调，以控制转录。我们的报告提供了对 ERV 衍生 lncRNA 以前未被认识的免疫基因调控机制的新见解。
