State Key Laboratory of Virology and Hubei Province Key Laboratory of Allergy and Immunology, Institute of Medical Virology, TaiKang Center for Life and Medical Sciences, TaiKang Medical School, Wuhan University, Wuhan, China.
School of Life Sciences, Hubei University, Wuhan, China.
PLoS Pathog. 2024 Feb 2;20(2):e1011999. doi: 10.1371/journal.ppat.1011999. eCollection 2024 Feb.
Hepatitis B virus (HBV) chronically infects 296 million people worldwide, posing a major global health threat. Export of HBV RNAs from the nucleus to the cytoplasm is indispensable for viral protein translation and genome replication, however the mechanisms regulating this critical process remain largely elusive. Here, we identify a key host factor embryonic lethal, abnormal vision, Drosophila-like 1 (ELAVL1) that binds HBV RNAs and controls their nuclear export. Using an unbiased quantitative proteomics screen, we demonstrate direct binding of ELAVL1 to the HBV pregenomic RNA (pgRNA). ELAVL1 knockdown inhibits HBV RNAs posttranscriptional regulation and suppresses viral replication. Further mechanistic studies reveal ELAVL1 recruits the nuclear export receptor CRM1 through ANP32A and ANP32B to transport HBV RNAs to the cytoplasm via specific AU-rich elements, which can be targeted by a compound CMLD-2. Moreover, ELAVL1 protects HBV RNAs from DIS3+RRP6+ RNA exosome mediated nuclear RNA degradation. Notably, we find HBV core protein is dispensable for HBV RNA-CRM1 interaction and nuclear export. Our results unveil ELAVL1 as a crucial host factor that regulates HBV RNAs stability and trafficking. By orchestrating viral RNA nuclear export, ELAVL1 is indispensable for the HBV life cycle. Our study highlights a virus-host interaction that may be exploited as a new therapeutic target against chronic hepatitis B.
乙型肝炎病毒（HBV）在全球范围内慢性感染 2.96 亿人，对全球健康构成重大威胁。HBV RNA 从细胞核输出到细胞质对于病毒蛋白翻译和基因组复制是必不可少的，但调节这一关键过程的机制在很大程度上仍未被揭示。在这里，我们鉴定了一种关键的宿主因子胚胎致死，异常视觉，果蝇样 1（ELAVL1），它可以结合 HBV RNA 并控制其核输出。通过使用无偏的定量蛋白质组学筛选，我们证明了 ELAVL1 与 HBV 前基因组 RNA（pgRNA）的直接结合。ELAVL1 敲低抑制 HBV RNA 的转录后调节并抑制病毒复制。进一步的机制研究表明，ELAVL1 通过 ANP32A 和 ANP32B 招募核输出受体 CRM1，通过特定的富含 AU 的元件将 HBV RNA 转运到细胞质中，这可以被一种化合物 CMLD-2 靶向。此外，ELAVL1 保护 HBV RNA 免受 DIS3+RRP6+RNA 核酶复合物介导的核 RNA 降解。值得注意的是，我们发现 HBV 核心蛋白对于 HBV RNA-CRM1 相互作用和核输出不是必需的。我们的结果揭示了 ELAVL1 作为一种关键的宿主因子，调节 HBV RNA 的稳定性和运输。通过协调病毒 RNA 的核输出，ELAVL1 对于 HBV 生命周期是不可或缺的。我们的研究强调了一种病毒-宿主相互作用，可能被用作治疗慢性乙型肝炎的新靶点。
