Center for Pathogen Biology and Infectious Diseases, Department of Immunology, Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, the First Hospital of Jilin University, Changchun, Jilin, China.
Department of Anesthesiology, the First Hospital of Jilin University, Changchun, Jilin, China.
mBio. 2022 Jun 28;13(3):e0067722. doi: 10.1128/mbio.00677-22. Epub 2022 May 19.
Hepatitis B virus (HBV)-related diseases are among the major diseases that affect millions of people worldwide. These diseases are difficult to eradicate and thus pose a serious global health challenge. There is an urgent need to understand the cross talk mechanism between HBV and the host. Cholesterol-25-hydroxylase (CH25H) and its enzymatic product, 25-hydroxycholesterol (25HC), were previously shown to exhibit effective broad-spectrum antiviral activity. However, the role of CH25H in the regulation of HBV infection and replication remains unclear. The present study reported increased expression of CH25H in HBV-infected patients compared to healthy subjects. Importantly, higher expression of CH25H expression was found to be associated with low HBV replication. Additionally, the present study aimed to identify CH25H mutants, which would lack hydroxylase activity but retain antiviral activity toward HBV infection and replication. Interestingly, it was observed that both CH25H and its mutants interacted with HBx protein and inhibited nuclear translocation of HBx. In particular, CH25H interacted with the C-terminal region of HBx, while transmembrane region 3 of CH25H was found to be critical for CH25H-HBx interaction and inhibition of HBV replication. The study results suggested that 25HC promoted HBV infection but not HBV replication. Thus, the results of the present study suggested the involvement of a dual mechanism in CH25H-mediated regulation of HBV replication. The study clearly demonstrated cross talk between HBV and the host through CH25H-HBx axis. The enzymatic product of CH25H, 25-hydroxycholesterol (25HC), has been previously shown to play a critical role in the blockage of the cell-virus fusion in response to viral infection. However, our study indicates a dual role of CH25H in regulating HBV. We find the CH25H-mediated inhibition of HBV replication is independent on its enzyme activity and CH25H binds to HBx and inhibits HBx nucleus translocation. We are interested to find out 25HC promotes HBV infection.
乙型肝炎病毒 (HBV) 相关疾病是影响全球数百万人的主要疾病之一。这些疾病难以根除，因此构成了严重的全球健康挑战。迫切需要了解 HBV 与宿主之间的串扰机制。胆固醇-25-羟化酶 (CH25H) 及其酶产物 25-羟胆固醇 (25HC) 先前表现出有效的广谱抗病毒活性。然而，CH25H 在调节 HBV 感染和复制中的作用尚不清楚。本研究报道了与健康受试者相比，HBV 感染患者中 CH25H 的表达增加。重要的是，发现 CH25H 表达水平升高与 HBV 复制水平降低有关。此外，本研究旨在鉴定缺乏羟化酶活性但保留对 HBV 感染和复制的抗病毒活性的 CH25H 突变体。有趣的是，观察到 CH25H 和其突变体均与 HBx 蛋白相互作用并抑制 HBx 的核转位。特别是，CH25H 与 HBx 的 C 端区域相互作用，而 CH25H 的跨膜区域 3 对于 CH25H-HBx 相互作用和抑制 HBV 复制至关重要。研究结果表明 25HC 促进 HBV 感染但不促进 HBV 复制。因此，本研究结果表明 CH25H 介导的 HBV 复制调节中存在双重机制。该研究通过 CH25H-HBx 轴清楚地表明了 HBV 与宿主之间的串扰。CH25H 的酶产物 25-羟胆固醇 (25HC) 先前已被证明在病毒感染时阻断细胞-病毒融合中起关键作用。然而，我们的研究表明 CH25H 在调节 HBV 中具有双重作用。我们发现 CH25H 介导的抑制 HBV 复制不依赖于其酶活性，并且 CH25H 与 HBx 结合并抑制 HBx 核转位。我们有兴趣了解 25HC 如何促进 HBV 感染。
