Yang Fan, Hu Feng, Song Hongxiao, Li Tie, Xu Fengchao, Xu Jing, Wang Le, Wang Fei, Zhu Yujia, Huang Mian, Gao Yanli, Rao Min, Ma Haichun, Tan Guangyun
Department of Hepatology, Center for Pathogen Biology and Infectious Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Anesthesiology, The First Hospital, Jilin University, Changchun, Jilin, China.
Front Immunol. 2025 Jan 13;15:1519639. doi: 10.3389/fimmu.2024.1519639. eCollection 2024.
The intricate link between cholesterol metabolism and host immune responses is well recognized, but the specific mechanisms by which cholesterol biosynthesis influences hepatitis B virus (HBV) replication remain unclear. In this study, we show that SREBP2, a key regulator of cholesterol metabolism, inhibits HBV replication by interacting directly with the HBx protein, thereby preventing its nuclear translocation. We also found that inhibiting the ER-to-Golgi transport of the SCAP-SREBP2 complex or blocking SREBP2 maturation significantly enhances HBV suppression. Notably, we demonstrate that the C-terminal domain (CTD) of SREBP2, rather than its N-terminal domain (NTD), mediates this inhibition by interacting with HBx and promoting its extracellular secretion, thus reducing nuclear HBx accumulation. These findings reveal a novel regulatory pathway that links cholesterol metabolism to HBV replication via SREBP2-mediated control of HBx localization. This insight provides a potential basis for new therapeutic strategies against HBV infection, addressing an important global health issue.
胆固醇代谢与宿主免疫反应之间的复杂联系已得到充分认识，但胆固醇生物合成影响乙型肝炎病毒（HBV）复制的具体机制仍不清楚。在本研究中，我们表明胆固醇代谢的关键调节因子SREBP2通过直接与HBx蛋白相互作用来抑制HBV复制，从而阻止其核转位。我们还发现，抑制SCAP-SREBP2复合物从内质网到高尔基体的转运或阻断SREBP2成熟可显著增强对HBV的抑制作用。值得注意的是，我们证明SREBP2的C末端结构域（CTD）而非其N末端结构域（NTD）通过与HBx相互作用并促进其细胞外分泌来介导这种抑制作用，从而减少核内HBx的积累。这些发现揭示了一条新的调节途径，即通过SREBP2介导的对HBx定位的控制将胆固醇代谢与HBV复制联系起来。这一见解为针对HBV感染的新治疗策略提供了潜在基础，解决了一个重要的全球健康问题。
