STAT3-Dependent Gene TRIM5γ Interacts With HBx Through a Zinc Binding Site on the BBox Domain.

Hongxiao Song,Xixi Fan,Bingxin Lei,Qingfei Xiao,Xiaolu Li,Guangyun Tan,Qi Wei,Fengchao Xu,Xiaoli Pang

doi:10.3389/fmicb.2021.663534

Abstract

Owing to its broad-spectrum antivirus activities, interferon (IFN) is an important alternative agent for use in the treatment of hepatitis B virus (HBV)-infected patients; however, the mechanism involved in the inhibition of HBV infection and replication by IFN remains unclear. We previously reported that the induction of TRIM5γ is important in the IFN treatment of HBV patients as it promotes the degradation of the HBx protein, while the manner in which TRIM5γ is induced by IFN and how TRIM5γ interacts with HBx remain unestablished until date. Our present findings confirmed the TRIM5γ-HBx-DDB1 interactions in the HBV-infected Primary human hepatocytes (PHH), and we further found that STAT3, and not STAT1, was responsible for the induction of TRIM5γ upon IFN stimulation and that the zinc binding site His123 on the BBOX domain was a decisive site in the interaction between TRIM5γ BBOX and HBx. In addition, based on the BBOX domain, we detected a 7-amino acid peptide with the potential of promoting HBx degradation and inhibiting HBV replication. On the other hand, we noted that the TRIM5γ expression was inhibited by HBV in chronically HBV infected patients. Thus, our study identified the crucial role of STAT3 in the induction of TRIM5γ, as well as proposed a 7-amino acid, small peptide as a potential candidate for the development of therapeutic agents targeting HBx.

Highlights

In response to most of the virus infection, interferon (IFN) is immediately induced and approximately 300 IFN-stimulated gene expression is further induced toward the inhibition of virus replication (Liu et al, 2012)
We questioned whether STAT1 is critical in the induction of TRIM5γ; TRIM5γ remained upregulated in the STAT1 knockout cells, which was the same cell line we used previously (Tan et al, 2018b)
PolydAdT, which was used as a DNA virus stimulation and induced huge amounts of interferon, was transfected into the WT or STAT1 or 3 KO cells, and as expected, TRIM5γ induction was noted in STAT1 but not in STAT3 KO cells (Figure 1G)

Summary

Introduction

In response to most of the virus infection, interferon (IFN) is immediately induced and approximately 300 IFN-stimulated gene expression is further induced toward the inhibition of virus replication (Liu et al, 2012). It has been reported that the IFN signaling is inhibited in HBV-infected patients (Cheng et al, 2017). Interferon therapy is an approved treatment modality for chronic HBV infection (Jacobson, 2006). The poor response and the substantial side-effects associated with this treatment affect its clinical utility. Besides nucleoside/nucleotide analog, there is currently no much effective treatment available for patients who respond poorly to IFN therapy (Tan et al, 2018a). IFNa14 was reported as the most effective IFN subtype in the inhibition of HBV cccDNA transcription and HBeAg/HBsAg

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Conclusion