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PGLYRP2 drives hepatocyte-intrinsic innate immunity by trapping and clearing hepatitis B virus

Ying LiInternational Research Center for Regenerative Medicine, Boao International Hospital, Qionghai, ChinaHuihui MaBiomedical Postgraduate Workstation of Heilongjiang Province, Harbin, ChinaYongjian ZhangDepartment of Surgery Oncology, Harbin Medical University Cancer Hospital, Harbin, ChinaTinghui HeSchool of Life Science and Technology, Harbin Institute of Technology, Harbin, ChinaBinyang LiBiomedical Postgraduate Workstation of Heilongjiang Province, Harbin, ChinaHaoran RenBiomedical Postgraduate Workstation of Heilongjiang Province, Harbin, ChinaJia FengSchool of Life Science and Technology, Harbin Institute of Technology, Harbin, ChinaJie ShengSchool of Life Science and Technology, Harbin Institute of Technology, Harbin, ChinaKai LiSchool of Medicine and Health, Harbin Institute of Technology, Harbin, ChinaQian YuSchool of Life Science and Technology, Harbin Institute of Technology, Harbin, ChinaYunfeng WangDepartment of Surgery Oncology, Harbin Medical University Cancer Hospital, Harbin, ChinaHaoran ZhaoDepartment of Surgery Oncology, Harbin Medical University Cancer Hospital, Harbin, ChinaJie HeSchool of Life Science and Technology, Harbin Institute of Technology, Harbin, ChinaHuicheng LiBiomedical Postgraduate Workstation of Heilongjiang Province, Harbin, ChinaHongjin WuInternational Research Center for Regenerative Medicine, Boao International Hospital, Qionghai, ChinaYuanfei YaoDepartment of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, ChinaMing ShiBiomedical Postgraduate Workstation of Heilongjiang Province, Harbin, China

2025en

ABI

Annotatsiya

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.

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Identifikatorlar

DOI: 10.1172/jci188083

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