Transforming growth factor \u03b2-activated kinase 1 transcriptionally suppresses hepatitis B virus replication

Geng Zhang,Ran Yan,Yong Lin,Haitao Guo,Zhanglian Xie,Mengji Lu,Jian Sun,Jinlin Hou,Libo Tang,Xiaoyong Zhang,Jinke Pang,Hongyan Liu

doi:10.1038/srep39901

Abstract

Hepatitis B Virus (HBV) replication in hepatocytes is restricted by the host innate immune system and related intracellular signaling pathways. Transforming growth factor β-activated kinase 1 (TAK1) is a key mediator of toll-like receptors and pro-inflammatory cytokine signaling pathways. Here, we report that silencing or inhibition of endogenous TAK1 in hepatoma cell lines leads to an upregulation of HBV replication, transcription, and antigen expression. In contrast, overexpression of TAK1 significantly suppresses HBV replication, while an enzymatically inactive form of TAK1 exerts no effect. By screening TAK1-associated signaling pathways with inhibitors and siRNAs, we found that the MAPK-JNK pathway was involved in TAK1-mediated HBV suppression. Moreover, TAK1 knockdown or JNK pathway inhibition induced the expression of farnesoid X receptor α, a transcription factor that upregulates HBV transcription. Finally, ectopic expression of TAK1 in a HBV hydrodynamic injection mouse model resulted in lower levels of HBV DNA and antigens in both liver and serum. In conclusion, our data suggest that TAK1 inhibits HBV primarily at viral transcription level through activation of MAPK-JNK pathway, thus TAK1 represents an intrinsic host restriction factor for HBV replication in hepatocytes.

Highlights

Hepatitis B virus (HBV) infection is a major health concern worldwide, causing a wide spectrum of liver diseases in more than 240 million people
To better define the mechanism whereby host factors restrain HBV, we investigated the impact of TAK1 and its downstream pathways on HBV replication and gene expression
We found that TAK1 suppresses HBV replication in HBV-producing cell lines, as well as in a hydrodynamic injection mouse model

Summary

Introduction

Hepatitis B virus (HBV) infection is a major health concern worldwide, causing a wide spectrum of liver diseases in more than 240 million people. Efficient control of HBV infection requires coordinated action of both innate and adaptive immunity Central to these antiviral responses is the secretion of IFNs or inflammatory cytokines, which promote specific T cell responses or target HBV-infected hepatocytes directly to limit virus infection[7]. Toll-like receptor (TLR) ligands, as well as other cytokines (interleukin IL-1β,IL-6 and transforming growth factor-β[TGF-β], etc.), activate multiple downstream signaling pathways to suppress HBV replication in hepatoma cells through the transcriptional regulation of HBV RNA10–13. These studies suggest that TLRs or cytokines, which relate to innate and adaptive immunity, play an active role in the intracellular control of HBV replication and gene expression in hepatocytes. It is of interest to study the potential function of TAK1, and the underlying mechanism, in the innate immune control of HBV replication

Methods

Results

Conclusion