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Roles Played by DOCK11, a Guanine Nucleotide Exchange Factor, in HBV Entry and Persistence in Hepatocytes
Ying-Yi Li1, Kazuhisa Murai2, Junyan Lyu2
1Department of Gastroenterology, Kanazawa University Graduate School of Medicine, 13-1, Takaramachi, Kanazawa 920-8640, Japan.
Viruses
|May 25, 2024
Summary
Dedicator of cytokinesis 11 (DOCK11) protein aids Hepatitis B virus (HBV) persistence by enabling viral DNA transcription and replication. Inhibiting DOCK11 with 10M-D42AN suppresses HBV, offering a potential therapeutic strategy for chronic hepatitis B.
Area of Science:
- Hepatology
- Virology
- Molecular Biology
Background:
- Hepatitis B virus (HBV) infection persistence is linked to viral covalently closed circular DNA (cccDNA).
- Dedicator of cytokinesis 11 (DOCK11), a guanine nucleotide exchange factor (GEF) for CDC42, is implicated in HBV persistence.
Purpose of the Study:
- To elucidate the role of DOCK11 in HBV replication and persistence.
- To investigate DOCK11's interaction with viral components and host cellular machinery.
- To evaluate DOCK11 inhibition as a therapeutic strategy for chronic hepatitis B (CHB).
Main Methods:
- Immunofluorescence and co-immunoprecipitation to study DOCK11 localization and interactions.
- Analysis of HBV replication and cccDNA transcription in the presence and absence of DOCK11.
- In vitro and in vivo studies using the DOCK11-binding peptide 10M-D42AN and entecavir.
Main Results:
- DOCK11 facilitates an alternative retrograde trafficking route for HBV from early endosomes to the trans-Golgi network and endoplasmic reticulum, evading lysosomal degradation.
- DOCK11 promotes HBV cccDNA transcription by associating it with H3K4me3 and RNA Polymerase II.
- DOCK11 is essential for cccDNA synthesis, and its inhibition by 10M-D42AN suppresses HBV replication.
- Combined treatment with 10M-D42AN and entecavir showed promising results in suppressing HBV.
Conclusions:
- DOCK11 is a critical host factor for HBV persistence, involved in viral trafficking, cccDNA transcription, and replication.
- Targeting DOCK11 with inhibitors like 10M-D42AN represents a potential therapeutic avenue for CHB.
- DOCK11 is a promising candidate molecule for developing targeted therapies against CHB.
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