Department of Microbiology and Immunology, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.
Department of Internal Medicine, Konkuk University School of Medicine, Seoul, 05030, Republic of Korea.
Cell Mol Biol Lett. 2023 Mar 30;28(1):26. doi: 10.1186/s11658-023-00440-1.
In our previous report, the rt269I type versus the rt269L type in genotype C2 infection led to poor clinical outcomes and enhanced mitochondrial stress in infected hepatocytes. Here, we sought to investigate differences between the rt269L and rt269I types in mitochondrial functionality in hepatitis B virus (HBV) genotype C2 infection, mainly focusing on endoplasmic reticulum (ER) stress-mediated autophagy induction as an upstream signal.
Mitochondrial functionality, ER stress signaling, autophagy induction, and apoptotic cell death between rt269L-type and rt269I-type groups were investigated via in vitro and in vivo experiments. Serum samples were collected from 187 chronic hepatitis patients who visited Konkuk or Seoul National University Hospital.
Our data revealed that genotype C rt269L versus rt269I infection led to improved mitochondrial dynamics and enhanced autophagic flux, mainly due to the activation of the PERK-eIF2α-ATF4 axis. Furthermore, we demonstrated that the traits found in genotype C rt269L infection were mainly due to increased stability of the HBx protein after deubiquitination. In addition, clinical data using patient sera from two independent Korean cohorts showed that, compared with rt269I, rt269L in infection led to lower 8-OHdG levels, further supporting its improved mitochondrial quality control.
Our data showed that, compared with the rt269I type, the rt269L type, which presented exclusively in HBV genotype C infection, leads to improved mitochondrial dynamics or bioenergetics, mainly due to autophagy induction via activation of the PERK-eIF2α-ATF4 axis in an HBx protein-dependent manner. This suggests that HBx stability and cellular quality control in the rt269L type predominating in genotype C endemic areas could at least partly contribute to some distinctive traits of genotype C infection, such as higher infectivity or longer duration of the hepatitis B e antigen (HBeAg) positive stage.
在我们之前的报告中，基因型 C2 感染中的 rt269I 型与 rt269L 型导致较差的临床结局，并增强了感染肝细胞中的线粒体应激。在这里，我们试图研究在乙型肝炎病毒（HBV）基因型 C2 感染中，rt269L 型与 rt269I 型之间在线粒体功能方面的差异，主要关注内质网（ER）应激介导的自噬诱导作为上游信号。
通过体外和体内实验研究了 rt269L 型和 rt269I 型之间的线粒体功能、ER 应激信号、自噬诱导和凋亡细胞死亡。收集了 187 名来自孔敬或首尔国立大学医院的慢性乙型肝炎患者的血清样本。
我们的数据表明，基因型 C 的 rt269L 与 rt269I 感染导致线粒体动力学改善和自噬流增强，主要是由于 PERK-eIF2α-ATF4 轴的激活。此外，我们证明了在基因型 C 的 rt269L 感染中发现的特征主要是由于去泛素化后 HBx 蛋白稳定性增加所致。此外，使用来自两个独立韩国队列的患者血清的临床数据表明，与 rt269I 相比，rt269L 感染导致更低的 8-OHdG 水平，进一步支持其改善的线粒体质量控制。
我们的数据表明，与 rt269I 型相比，在 HBV 基因型 C 感染中仅出现的 rt269L 型主要通过 PERK-eIF2α-ATF4 轴的激活诱导自噬，从而导致线粒体动力学或生物能学的改善，这主要是由于 HBx 蛋白依赖性的。这表明在基因型 C 流行地区占主导地位的 rt269L 型的 HBx 稳定性和细胞质量控制至少部分导致了基因型 C 感染的一些独特特征，例如更高的感染性或更长的乙型肝炎 e 抗原（HBeAg）阳性期持续时间。
