The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
Department of Epidemiology, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
Hepatology. 2019 May;69(5):1885-1902. doi: 10.1002/hep.30497. Epub 2019 Mar 15.
Hepatitis B virus (HBV) infection is a common infectious disease, in which nuclear covalently closed circular DNA (cccDNA) plays a key role in viral persistence, viral reactivation after treatment withdrawal, and drug resistance. A recent genome-wide association study has identified that the ubiquitin conjugating enzyme E2 L3 (UBE2L3) gene is associated with increased susceptibility to chronic HBV (CHB) infection in adults. However, the association between UBE2L3 and children with CHB and the underlying mechanism remain unclear. In this study, we performed two-stage case-control studies including adults and independent children in the Chinese Han population. The rs59391722 allele in the promoter of the UBE2L3 gene was significantly associated with HBV infection in both adults and children, and it increased the promoter activity of UBE2L3. Serum UBE2L3 protein levels were positively correlated with HBV viral load and hepatitis B e antigen (HBeAg) levels in children with CHB. In an HBV infection cell model, UBE2L3 knockdown significantly reduced total HBV RNAs, 3.5-kb RNA, as well as cccDNA in HBV-infected HepG2-Na /taurocholate cotransporting polypeptide cells and human primary hepatocytes. A mechanistic study found that UBE2L3 maintained cccDNA stability by inducing proteasome-dependent degradation of apolipoprotein B mRNA editing enzyme catalytic subunit 3A, which is responsible for the degradation of HBV cccDNA. Moreover, interferon-α (IFN-α) treatment markedly decreased UBE2L3 expression, while UBE2L3 silencing reinforced the antiviral activity of IFN-α on HBV RNAs, cccDNA, and DNA. rs59391722 in UBE2L3 was correlated with HBV DNA suppression and HBeAg loss in response to IFN-α treatment of children with CHB. Conclusion: These findings highlight a host gene, UBE2L3, contributing to the susceptibility to persistent HBV infection; UBE2L3 may be involved in IFN-mediated viral suppression and serve as a potential target in the prevention and treatment of HBV infection.
乙型肝炎病毒（HBV）感染是一种常见的传染病，其中核共价闭合环状 DNA（cccDNA）在病毒持续存在、治疗停药后病毒再激活以及耐药性方面发挥着关键作用。最近的全基因组关联研究表明，泛素连接酶 E2 L3（UBE2L3）基因与成人慢性乙型肝炎（CHB）感染的易感性增加有关。然而，UBE2L3 与儿童 CHB 的关联以及潜在机制尚不清楚。在这项研究中，我们在中国汉族人群中进行了包括成人和独立儿童在内的两阶段病例对照研究。UBE2L3 基因启动子中的 rs59391722 等位基因与成人和儿童的 HBV 感染均显著相关，并增加了 UBE2L3 的启动子活性。CHB 患儿血清 UBE2L3 蛋白水平与 HBV 病毒载量和乙型肝炎 e 抗原（HBeAg）水平呈正相关。在 HBV 感染细胞模型中，UBE2L3 敲低显著降低了 HBV 感染 HepG2-Na / taurocholate cotransporting polypeptide 细胞和人原代肝细胞中的总 HBV RNA、3.5-kb RNA 和 cccDNA。一项机制研究发现，UBE2L3 通过诱导载脂蛋白 B mRNA 编辑酶催化亚基 3A 的蛋白酶体依赖性降解来维持 cccDNA 的稳定性，该亚基负责降解 HBV cccDNA。此外，干扰素-α（IFN-α）治疗显著降低 UBE2L3 的表达，而 UBE2L3 沉默增强了 IFN-α 对 HBV RNA、cccDNA 和 DNA 的抗病毒活性。UBE2L3 中的 rs59391722 与 CHB 患儿 IFN-α 治疗后的 HBV DNA 抑制和 HBeAg 丢失相关。结论：这些发现强调了宿主基因 UBE2L3 导致对持续 HBV 感染的易感性；UBE2L3 可能参与 IFN 介导的病毒抑制，可作为预防和治疗 HBV 感染的潜在靶点。
