Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, 44195, USA.
Florida Research and Innovation Center, Cleveland Clinic Foundation, Port St. Lucie, FL, 34987, USA.
Nat Commun. 2023 Jun 9;14(1):3385. doi: 10.1038/s41467-023-39091-3.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, generates multiple protein-coding, subgenomic RNAs (sgRNAs) from a longer genomic RNA, all bearing identical termini with poorly understood roles in regulating viral gene expression. Insulin and interferon-gamma, two host-derived, stress-related agents, and virus spike protein, induce binding of glutamyl-prolyl-tRNA synthetase (EPRS1), within an unconventional, tetra-aminoacyl-tRNA synthetase complex, to the sgRNA 3'-end thereby enhancing sgRNA expression. We identify an EPRS1-binding sarbecoviral pan-end activating RNA (SPEAR) element in the 3'-end of viral RNAs driving agonist-induction. Translation of another co-terminal 3'-end feature, ORF10, is necessary for SPEAR-mediated induction, independent of Orf10 protein expression. The SPEAR element enhances viral programmed ribosomal frameshifting, thereby expanding its functionality. By co-opting noncanonical activities of a family of essential host proteins, the virus establishes a post-transcriptional regulon stimulating global viral RNA translation. A SPEAR-targeting strategy markedly reduces SARS-CoV-2 titer, suggesting a pan-sarbecoviral therapeutic modality.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）是 COVID-19 的病原体，它从较长的基因组 RNA 生成多个编码蛋白质的亚基因组 RNA（sgRNA），所有 sgRNA 都具有相同的末端，但在调节病毒基因表达方面的作用知之甚少。胰岛素和干扰素-γ这两种宿主来源的应激相关因子，以及病毒刺突蛋白，诱导谷氨酰-脯氨酰-tRNA 合成酶（EPRS1）在非常规的四氨酰-tRNA 合成酶复合物内与 sgRNA 3' 端结合，从而增强 sgRNA 的表达。我们在驱动激动剂诱导的病毒 RNA 的 3' 端鉴定了一个 EPRS1 结合的沙贝科病毒泛末端激活 RNA（SPEAR）元件。另一个共末端 3' 端特征 ORF10 的翻译对于 SPEAR 介导的诱导是必需的，而不依赖于 Orf10 蛋白表达。SPEAR 元件增强了病毒的程序性核糖体移码，从而扩大了其功能。通过利用一组必需宿主蛋白的非典型活性，病毒建立了一个转录后调节子，刺激全球病毒 RNA 翻译。针对 SPEAR 的策略显著降低了 SARS-CoV-2 的滴度，表明这是一种泛沙贝科病毒的治疗模式。
