State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei Province, China.
University of Chinese Academy of Sciences, Beijing, China.
J Virol. 2023 May 31;97(5):e0058023. doi: 10.1128/jvi.00580-23. Epub 2023 May 11.
Hepatitis B virus (HBV) infection affects hepatic metabolism. Serum metabolomics studies have suggested that HBV possibly hijacks the glycerol-3-phosphate (G3P) shuttle. In this study, the two glycerol-3-phosphate dehydrogenases (GPD1 and GPD2) in the G3P shuttle were analyzed for determining their role in HBV replication and the findings revealed that GPD2 and not GPD1 inhibited HBV replication. The knockdown of GPD2 expression upregulated HBV replication, while GPD2 overexpression reduced HBV replication. Moreover, the overexpression of GPD2 significantly reduced HBV replication in hydrodynamic injection-based mouse models. Mechanistically, this inhibitory effect is related to the GPD2-mediated degradation of HBx protein by recruiting the E3 ubiquitin ligase TRIM28 and not to the alterations in G3P metabolism. In conclusion, this study revealed GPD2, a key enzyme in the G3P shuttle, as a host restriction factor in HBV replication. The glycerol-3-phosphate (G3P) shuttle is important for the delivery of cytosolic reducing equivalents into mitochondria for oxidative phosphorylation. The study analyzed two key components of the G3P shuttle and identified GPD2 as a restriction factor in HBV replication. The findings revealed a novel mechanism of GPD2-mediated inhibition of HBV replication via the recruitment of TRIM28 for degrading HBx, and the HBx-GPD2 interaction could be another potential therapeutic target for anti-HBV drug development.
乙型肝炎病毒 (HBV) 感染会影响肝脏的代谢。血清代谢组学研究表明，HBV 可能劫持甘油-3-磷酸 (G3P) 穿梭。在这项研究中，分析了 G3P 穿梭中的两种甘油-3-磷酸脱氢酶 (GPD1 和 GPD2)，以确定它们在 HBV 复制中的作用，研究结果表明 GPD2 而不是 GPD1 抑制 HBV 复制。GPD2 表达的敲低上调了 HBV 复制，而 GPD2 过表达则降低了 HBV 复制。此外，GPD2 的过表达在基于水力注射的小鼠模型中显著降低了 HBV 复制。从机制上讲，这种抑制作用与 GPD2 通过招募 E3 泛素连接酶 TRIM28 介导的 HBx 蛋白降解有关，而与 G3P 代谢的改变无关。总之，这项研究揭示了 G3P 穿梭中的关键酶 GPD2 是 HBV 复制中的宿主限制因子。甘油-3-磷酸 (G3P) 穿梭对于将细胞质还原当量输送到线粒体进行氧化磷酸化很重要。该研究分析了 G3P 穿梭的两个关键组成部分，并确定 GPD2 是 HBV 复制的限制因子。研究结果揭示了 GPD2 通过招募 TRIM28 降解 HBx 来介导抑制 HBV 复制的新机制，HBx-GPD2 相互作用可能是开发抗 HBV 药物的另一个潜在治疗靶点。
