TGF-β triggers HBV cccDNA degradation through AID-dependent deamination

Ying Qiao; Xiaoxu Han; Gefei Guan; Na Wu; Jianbo Sun; Vladimir Pak; Guoxin Liang

doi:10.1002/1873-3468.12058

TGF-β triggers HBV cccDNA degradation through AID-dependent deamination

FEBS Lett. 2016 Feb;590(3):419-27. doi: 10.1002/1873-3468.12058. Epub 2016 Feb 2.

Authors

Ying Qiao¹, Xiaoxu Han², Gefei Guan³, Na Wu¹, Jianbo Sun⁴, Vladimir Pak⁵, Guoxin Liang²

Affiliations

¹ The Core Laboratory for Public Health Science and Practice, The First Affiliated Hospital, China Medical University, Shenyang, China.
² Key Laboratory of AIDS Immunology of the National Health and Family Planning Commission, Department of Laboratory Medicine, The First Affiliated Hospital, China Medical University, Shenyang, China.
³ Department of Neurosurgery, The First Affiliated Hospital, China Medical University, Shenyang, China.
⁴ Department of Microbiology and Immunology, Columbia University, New York, NY, USA.
⁵ Department of Medicine, Microbiology and Immunology, University of California, San Francisco, CA, USA.

PMID: 26867650
DOI: 10.1002/1873-3468.12058

Abstract

The covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is a viral center molecule for HBV infection and persistence. However, the cellular restriction factors of HBV cccDNA are not well understood. Here, we show that TGF-β can induce nuclear viral cccDNA degradation and hypermutation via activation-induced cytidine deaminase (AID) deamination activity in hepatocytes. This suppression by TGF-β is abrogated when AID or the activity of uracil-DNA glycosylase (UNG) is absent, which indicates that AID deamination and the UNG-mediated excision of uracil act in concert to degrade viral cccDNA. Moreover, the HBV core protein promotes the interaction between AID and viral cccDNA. Overall, our results indicate a novel molecular mechanism that allows cytokine TGF-β to restrict viral nuclear cccDNA in innate immunity, thereby suggesting a novel method for potentially eliminating cccDNA.

Keywords: AID; HBV; Hypermutation; UNG; cccDNA.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Cell Nucleus / drug effects
Cell Nucleus / immunology
Cell Nucleus / metabolism
Cell Nucleus / virology
Chromatin Immunoprecipitation
Cytidine Deaminase / antagonists & inhibitors
Cytidine Deaminase / genetics
Cytidine Deaminase / metabolism*
DNA, Circular / isolation & purification
DNA, Circular / metabolism*
DNA, Viral / isolation & purification
DNA, Viral / metabolism*
Deamination / drug effects
Enzyme Inhibitors / pharmacology
Hepatitis B virus / drug effects
Hepatitis B virus / immunology
Hepatitis B virus / metabolism*
Hepatocytes / drug effects
Hepatocytes / immunology
Hepatocytes / metabolism
Hepatocytes / virology*
Humans
Hydrolysis / drug effects
Immunity, Innate / drug effects
Mutation
RNA Interference
RNA, Small Interfering
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism
Transforming Growth Factor beta / metabolism*
Uracil-DNA Glycosidase / antagonists & inhibitors
Uracil-DNA Glycosidase / metabolism*
Viral Core Proteins / genetics
Viral Core Proteins / metabolism

Substances

DNA, Circular
DNA, Viral
Enzyme Inhibitors
RNA, Small Interfering
Recombinant Proteins
Transforming Growth Factor beta
Viral Core Proteins
Uracil-DNA Glycosidase
AICDA (activation-induced cytidine deaminase)
Cytidine Deaminase