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-b can induce nuclear viral cccDNA degradation and hypermutation via activation-induced cytidine deaminase (AID) deamination activity in hepatocytes. This suppression by TGF-b 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-b to restrict viral nuclear cccDNA in innate immunity, thereby suggesting a novel method for potentially eliminating cccDNA.Keywords: AID; cccDNA; HBV; Hypermutation; UNG Highlights • AID triggers HBV cccDNA degradation via its deamination activity.• AID induces viral cccDNA hypermutation.• TGF-b reduces viral cccDNA through AID in hepatocytes.Almost 350 million people who are chronically infected with hepatitis B virus (HBV) worldwide are at high risk of developing liver cirrhosis and hepatocellular carcinoma. Thus, HBV infection is a major global health concern [1-3]. The covalently closed circular DNA (cccDNA) of HBV plays an essential role in virus replication and persistence. After entry into the hepatocytes, HBV first forms cccDNA in the host cell's nucleus before transcribing viral RNAs, including a replicative RNA intermediate called pregenomic (pg) RNA that encodes two viral proteins, HBV core (HBc), and HBV polymerase (Pol), which encapsidate pgRNA to form a nucleocapsid. HBV Pol reverse transcribes pgRNA to produce relaxed circular DNA

Alteration of microRNA profiles by a novel inhibitor of human La protein in HBV‐transformed human hepatoma cells

“…44 Most recently, TGF-β was found to trigger HBV cccDNA degradation through AIDdependent deamination. 45 In summary, our study showed that the novel La inhibitor HBSC11 upregulated the expression of three miRNAs (miR-3912-5p, miR-6793-5p, and miR-7159-5p) in HepG2.2.15 cells. HBSC11 may affect a number of genes that are involved in the regulation of the TGF-β, Wnt, and p53 signaling pathways.…”

“…TGF‐β has been shown to induce expression at the mRNA level of multiple TGF‐β/BMP pathway genes, possibly governed by TGF‐β‐induced miRNA expression (eg, hsa‐miR‐125a‐5p), thus decreasing both HBV mRNA and DNA expression . Most recently, TGF‐β was found to trigger HBV cccDNA degradation through AID‐dependent deamination …”

Revisiting Hepatitis B Virus: Challenges of Curative Therapies

“…TGF-␤ could also induce cccDNA deamination and degradation in hepatocytes via activation-induced cytidine deaminase (AID) (176), which has been described to mediate degradation of duck HBV (DHBV) cccDNA (177). The effect elicited by TGF-␤ was abrogated when AID or the activity of uracil N-glycosylase (UNG) was blocked, indicating that AID-mediated deamination and the excision of uracil by UNG act in concert to degrade HBV cccDNA (176). Similar to the case for A3A, the interaction between AID and viral cccDNA is mediated by HBc.…”

AID recruits the RNA exosome to degrade HIV‐1 nascent transcripts through interaction with the Tat‐P‐TEFb‐TAR RNP complex

“…The RNA exosome has been shown to bind to AID, causing the cleavage of nascent RNA of immunoglobulins and HBV [20,[26][27][28]. The RNA exosome has been shown to bind to AID, causing the cleavage of nascent RNA of immunoglobulins and HBV [20,[26][27][28].…”

“…Next, we examined the molecular mechanism of AIDmediated suppression of HIV-1 transcripts. The RNA exosome has been shown to bind to AID, causing the cleavage of nascent RNA of immunoglobulins and HBV [20,[26][27][28]. Thus, we hypothesized that AID may also act as an adaptor that recruits the RNA exosome The cells in (B) were treated with EU for 1 h to label nascent RNA.…”