HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, 20892, USA.
CCR Collaborative Bioinformatics Resource, National Cancer Institute, Bethesda, 20892, USA.
EMBO Rep. 2024 Mar;25(3):1541-1569. doi: 10.1038/s44319-023-00051-z. Epub 2024 Jan 23.
To globally profile circRNAs, we employ RNA-Sequencing paired with chimeric junction analysis for alpha-, beta-, and gamma-herpesvirus infection. We find circRNAs are, as a population, resistant to host shutoff. We validate this observation using ectopic expression assays of human and murine herpesvirus endoribonucleases. During lytic infection, four circRNAs are commonly induced across all subfamilies of human herpesviruses, suggesting a shared mechanism of regulation. We test one such mechanism, namely how interferon-stimulation influences circRNA expression. 67 circRNAs are upregulated by either interferon-β or -γ treatment, with half of these also upregulated during lytic infection. Using gain and loss of function studies we find an interferon-stimulated circRNA, circRELL1, inhibits lytic Herpes Simplex Virus-1 infection. We previously reported circRELL1 inhibits lytic Kaposi sarcoma-associated herpesvirus infection, suggesting a pan-herpesvirus antiviral activity. We propose a two-pronged model in which interferon-stimulated genes may encode both mRNA and circRNA with antiviral activity. This is critical in cases of host shutoff, such as alpha- and gamma-herpesvirus infection, where the mRNA products are degraded but circRNAs escape.
为了全面描绘 circRNA 图谱，我们采用 RNA 测序结合嵌合连接分析技术，研究了 α、β 和 γ 疱疹病毒感染。我们发现 circRNA 作为一个群体，能够抵抗宿主关闭。我们使用人类和鼠类疱疹病毒内切核酸酶的异位表达实验验证了这一观察结果。在裂解感染过程中，所有人类疱疹病毒亚科中共有四种 circRNA 被普遍诱导，这表明存在一种共同的调控机制。我们对其中一种机制进行了测试，即干扰素刺激如何影响 circRNA 的表达。β 或 γ 干扰素处理可上调 67 种 circRNA，其中一半在裂解感染过程中也被上调。通过增益和缺失功能研究，我们发现一种干扰素刺激的 circRNA，circRELL1，可抑制单纯疱疹病毒 1 的裂解感染。我们之前曾报道 circRELL1 可抑制卡波西肉瘤相关疱疹病毒的裂解感染，这表明它具有泛疱疹病毒的抗病毒活性。我们提出了一个双重模型，即干扰素刺激的基因可能编码具有抗病毒活性的 mRNA 和 circRNA。在宿主关闭的情况下，这一点至关重要，例如在 α 和 γ 疱疹病毒感染中，mRNA 产物会被降解，但 circRNA 则会逃逸。
