The mitochondrial GTPase ERAL1 inhibits HBV replication by triggering the MAVS signaling cascade.

BACKGROUND AND AIMS: Mitochondrial GTPase ERA G-protein-like 1 (ERAL1) is considered an antiviral host factor against RNA viruses. However, its role in driving DNA virus infection, particularly hepatitis B virus (HBV) infection, and its relevance to human liver disease are unknown. This study aimed to define the function and molecular mechanism of ERAL1 in HBV pathogenesis.

METHODS

Complementary models, including HBV-replicating cell lines, an rAAV8-HBV hydrodynamic mouse model, and clinical samples from patients across the natural history of chronic HBV infection were employed and analyzed via coimmunoprecipitation, confocal immunofluorescence, RNA sequencing, qPCR, immunoblotting, and immunohistochemistry.

RESULTS

ERAL1 expression was significantly suppressed in HBV patients, including an approximately 75% reduction in the livers of patients during the immune-reactive phase compared with those in healthy controls. ERAL1 overexpression resulted in notable antiviral activity, suppressed HBV replication and achieved nearly 60% HBsAg clearance in vivo. Mechanistically, ERAL1 interacts with mitochondrial adaptor MAVS, promoting its aggregation and subsequently activating the downstream Akt and MAPK signaling pathways, which are essential for its antiviral effect.

CONCLUSIONS

ERAL1 is identified as a crucial HBV-restricting host factor and a novel mitochondria-centered defense mechanism in which ERAL1 reinforces MAVS-dependent antiviral signaling. The notable downregulation of ERAL1 in patient livers and its considerable antiviral effectiveness suggest that ERAL1 is a candidate host factor worthy of further therapeutic exploration.