CRM1 介导的乙型肝炎病毒包膜病毒 RNA 的核输出。

CRM1-spike-mediated nuclear export of hepatitis B virus encapsidated viral RNA.

机构信息

Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei 112, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.

Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.

出版信息

Cell Rep. 2022 Mar 8;38(10):110472. doi: 10.1016/j.celrep.2022.110472.

DOI:10.1016/j.celrep.2022.110472

PMID:35263598

Abstract

Hepatitis B virus (HBV) is a global pathogen. We report here that the cellular CRM1 machinery can mediate nuclear export of entire HBV core (HBc) particles containing encapsidated viral RNAs. Two CRM1-mediated nuclear export signals (NES) cluster at the conformationally flexible spike tips of HBc particles. Mutant NES capsids exhibit strongly reduced associations with CRM1 and nucleoporin358 in vivo. CRM1 and NXF1 machineries mediate nuclear export of HBc particles independently. Inhibition of nuclear export has pleiotropic consequences, including nuclear accumulation of HBc particles, a significant reduction of encapsidated viral RNAs in the cytoplasm but not in the nucleus, and barely detectable viral DNA. We hypothesize an HBV life cycle where encapsidation of the RNA pregenome can initiate early in the nucleus, whereas DNA genome maturation occurs mainly in the cytoplasm. We identified a druggable target for HBV by blocking its intracellular trafficking.

摘要

乙型肝炎病毒 (HBV) 是一种全球性病原体。我们在这里报告，细胞 CRM1 机制可以介导含有包裹病毒 RNA 的整个乙型肝炎核心 (HBc) 颗粒的核输出。两个 CRM1 介导的核输出信号 (NES) 聚集在 HBc 颗粒构象灵活的刺突尖端。突变的 NES 衣壳在体内与 CRM1 和核孔蛋白 358 的结合显著减少。CRM1 和 NXF1 机制独立介导 HBc 颗粒的核输出。核输出的抑制会产生多种后果，包括 HBc 颗粒在核内的积累，细胞质中包裹的病毒 RNA 显著减少，但核内没有，以及几乎检测不到的病毒 DNA。我们假设 HBV 生命周期中，RNA 前基因组的包裹可以在核内早期开始，而 DNA 基因组成熟主要发生在细胞质中。我们通过阻断其细胞内运输，鉴定了一个可用于治疗 HBV 的靶点。