Li Ying, Ma Huihui, Zhang Yongjian, He Tinghui, Li Binyang, Ren Haoran, Feng Jia, Sheng Jie, Li Kai, Qian Yu, Wang Yunfeng, Zhao Haoran, He Jie, Li Huicheng, Wu Hongjin, Yao Yuanfei, Shi Ming
School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
International Research Center for Regenerative Medicine, Boao International Hospital, Qionghai, China.
J Clin Invest. 2025 Feb 13;135(8). doi: 10.1172/JCI188083. eCollection 2025 Apr 15.
Spontaneous clearance of hepatitis B virus (HBV) is frequent in adults (95%) but rare in infants (5%), emphasizing the critical role of age-related hepatic immunocompetence. However, the underlying mechanisms of hepatocyte-specific immunosurveillance and age-dependent HBV clearance remain unclear. Here, we identified PGLYRP2 as a hepatocyte-specific pattern recognition receptor with age-dependent expression, and demonstrated that phase separation of PGLYRP2 was a critical driver of spontaneous HBV clearance in hepatocytes. Mechanistically, PGLYRP2 recognized and potentially eliminated covalently closed circular DNA via phase separation, coordinated by its intrinsically disordered region and HBV DNA-binding domain (PGLYRP2IDR/209-377) in the nucleus. Additionally, PGLYRP2 suppressed HBV capsid assembly by directly interacting with the viral capsid, mediated by its PGRP domain. This interaction promoted the nucleocytoplasmic translocation of PGLYRP2 and subsequent secretion of the PGLYRP2/HBV capsid complex, thereby bolstering the hepatic antiviral response. Pathogenic variants or deletions in PGLYRP2 impaired its ability to inhibit HBV replication, highlighting its essential role in hepatocyte-intrinsic immunity. These findings suggest that targeting the PGLYRP2-mediated host-virus interaction may offer a potential therapeutic strategy for the development of anti-HBV treatments, representing a promising avenue for achieving a functional cure for HBV infection.
乙肝病毒（HBV）在成人中常可自发清除（95%），但在婴儿中则很少见（5%），这凸显了年龄相关的肝脏免疫能力的关键作用。然而，肝细胞特异性免疫监视以及年龄依赖性HBV清除的潜在机制仍不清楚。在此，我们鉴定出PGLYRP2是一种具有年龄依赖性表达的肝细胞特异性模式识别受体，并证明PGLYRP2的相分离是肝细胞中HBV自发清除的关键驱动因素。从机制上来说，PGLYRP2通过相分离识别并可能清除共价闭合环状DNA，这一过程由其位于细胞核内的内在无序区域和HBV DNA结合结构域（PGLYRP2IDR/209 - 377）协同完成。此外，PGLYRP2通过其PGRP结构域直接与病毒衣壳相互作用，从而抑制HBV衣壳组装。这种相互作用促进了PGLYRP2的核质转运以及随后PGLYRP2/HBV衣壳复合物的分泌，进而增强肝脏的抗病毒反应。PGLYRP2中的致病变异或缺失会损害其抑制HBV复制的能力，突出了其在肝细胞固有免疫中的重要作用。这些发现表明，靶向PGLYRP2介导的宿主 - 病毒相互作用可能为开发抗HBV治疗提供一种潜在的治疗策略，这是实现功能性治愈HBV感染的一个有前景的途径。
