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GBP2 counteracts interferon therapy by stabilizing HBx to promote HBV replication and progression
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DOI：10.1007/s00018-026-06394-9.png)
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Abstract
En 中文
Type I interferon (IFN-I) is widely used for the treatment of hepatitis B virus (HBV) infection, yet its therapeutic efficacy remains limited. Here, we identify guanylate-binding protein 2 (GBP2), an interferon-stimulated gene, as a host factor that paradoxically promotes HBV replication. GBP2 overexpression stabilized the viral regulatory protein HBx and markedly prolonged its half-life, whereas GBP2 knockdown facilitated HBx degradation. Mechanistically, GBP2 recruited the E3 ligase HUWE1 to induce K29-linked ubiquitination of HBx at lysine 95, which in turn suppressed K48-linked ubiquitination and proteasomal degradation. Functionally, GBP2-mediated HBx stabilization enhanced HBV replication and promoted hepatoma cell migration and invasion. Importantly, GBP2 expression was elevated in PBMCs of HBV-infected patients and further induced by IFN-I treatment, while HBV delayed early IFN-mediated GBP2 induction in HBV-containing hepatocyte-derived cells. Together, these findings reveal a novel mechanism by which GBP2 antagonizes the antiviral activity of IFN-I by stabilizing HBx, thereby facilitating HBV replication and potentially contributing to hepatocarcinogenesis. In brief, IFN activates ISGF3 via the JAK-STAT signaling pathway to produce the IFN-stimulating gene, GBP2, which promotes the K29 chain ubiquitination of HBx protein on the K95 site, which in turn competitively inhibits the K48 chain ubiquitination of HBx, thereby inhibiting HBx protein degradation. In brief, IFN activates ISGF3 via the JAK-STAT signaling pathway to produce the IFN-stimulating gene, GBP2, which promotes the K29 chain ubiquitination of HBx protein on the K95 site, which in turn competitively inhibits the K48 chain ubiquitination of HBx, thereby inhibiting HBx protein degradation.
Keywords:
Interferon
GBP2
HBV
HUWE1
HBx protein
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