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Updated: Sep 26, 2026
Identifying Inhibitors of the HBx-DDB1 Interaction Using a Split Luciferase Assay System
Published on: December 21, 2019
Hepatitis B virus X protein and simian virus 5 V protein exhibit similar UV-DDB1 binding properties to mediate
Olivier Leupin1, Séverine Bontron, Michel Strubin
1Department of Genetics and Microbiology, University Medical Centre (C.M.U.), 1211 Geneva 4, Switzerland.
Abstract:
The UV-damaged DNA-binding activity protein (UV-DDB) consists of two subunits, DDB1 and DDB2, and functions in DNA repair and cell cycle regulation. The DDB1 subunit is a target for the hepatitis B virus X protein (HBx). Binding of HBx to DDB1 interferes with cell growth and viability in culture and has been implicated in the establishment of viral infection. DDB1 also interacts with the V proteins encoded by several paramyxoviruses including simian virus 5 (SV5), which prevent interferon signaling by targeting either STAT1 or STAT2 proteins for proteolysis. The role of V binding to DDB1, however, remains unclear. Here we show that the V protein of SV5 (SV5-V) and HBx exhibit strikingly similar DDB1 binding properties. Thus, SV5-V and HBx bind to DDB1 in a mutually exclusive manner, and SV5-V shares with HBx the ability to enhance the steady-state levels of DDB1 and to inhibit its association with DDB2. Yet only HBx induces cell death, and SV5-V can prevent HBx from doing so by blocking its interaction with DDB1. Binding of SV5-V to DDB1 may serve another function, since SV5-V shows a decreased ability to induce STAT1 degradation in cells expressing reduced amounts of DDB1. These findings demonstrate that HBx performs a unique function through its association with DDB1 for which SV5-V cannot substitute and suggest that SV5-V and HBx have evolved to bind DDB1 to achieve distinct functions, both by a mechanism that does not involve DDB2.
Insights
Hepatitis B virus X protein (HBx) and simian virus 5 V protein (SV5-V) bind DDB1 differently. While both bind mutually exclusively, only HBx causes cell death, and SV5-V can block this effect.
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- The UV-damaged DNA-binding activity protein (UV-DDB) complex, comprising DDB1 and DDB2, is crucial for DNA repair and cell cycle control.
- The hepatitis B virus X protein (HBx) targets DDB1, impacting cell viability and viral infection establishment.
- Paramyxovirus V proteins, like SV5-V, interact with DDB1 to disrupt interferon signaling, but their precise role remains unclear.
Purpose of the Study:
- To investigate the functional consequences of DDB1 binding by SV5-V compared to HBx.
- To elucidate the distinct roles of DDB1 interactions with viral proteins.
- To determine if SV5-V binding to DDB1 can substitute for HBx functions.
Main Methods:
- Comparative analysis of DDB1 binding properties between SV5-V and HBx.
- Assessment of DDB1 and DDB2 association dynamics.
- Evaluation of cell viability and STAT1/STAT2 degradation in response to viral protein expression and DDB1 levels.
Main Results:
- SV5-V and HBx bind to DDB1 in a mutually exclusive manner.
- Both SV5-V and HBx enhance DDB1 levels and inhibit DDB1-DDB2 association.
- Only HBx induces cell death; SV5-V prevents HBx-induced cell death by blocking DDB1 interaction. SV5-V's STAT1 degradation ability is DDB1-dependent.
Conclusions:
- HBx and SV5-V bind DDB1 via distinct mechanisms to achieve separate functions.
- SV5-V binding to DDB1 does not replicate HBx's cell death-inducing function.
- DDB1 interaction is critical for both viral protein functions, but HBx's role in cell death is unique and not substituted by SV5-V.
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