title: TGF-β triggers HBV cccDNA degradation through AID-dependent deamination.
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.
authors: The Core Laboratory for Public Health Science and Practice, The First Affiliated Hospital, China Medical University, Shenyang, China.
authors: Ying
authors: Y
authors: Qiao
authors: 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.
authors: Xiaoxu
authors: X
authors: Han
authors: Department of Neurosurgery, The First Affiliated Hospital, China Medical University, Shenyang, China.
authors: Gefei
authors: G
authors: Guan
authors: The Core Laboratory for Public Health Science and Practice, The First Affiliated Hospital, China Medical University, Shenyang, China.
authors: Na
authors: N
authors: Wu
authors: Department of Microbiology and Immunology, Columbia University, New York, NY, USA.
authors: Jianbo
authors: J
authors: Sun
authors: Department of Medicine, Microbiology and Immunology, University of California, San Francisco, CA, USA.
authors: Vladimir
authors: V
authors: Pak
authors: 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.
authors: Guoxin
authors: G
authors: Liang
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology; D047369:Chromatin Immunoprecipitation; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004270:DNA, Circular / Q000302:isolation & purification / Q000378:metabolism*; D004279:DNA, Viral / Q000302:isolation & purification / Q000378:metabolism*; D003641:Deamination / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006515:Hepatitis B virus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007113:Immunity, Innate / Q000187:drug effects; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D051981:Uracil-DNA Glycosidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D004270:DNA, Circular; D004279:DNA, Viral; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014758:Viral Core Proteins; D051981:Uracil-DNA Glycosidase; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase
keywords: AID; HBV; Hypermutation; UNG; cccDNA