Human Hepatitis B Viral e Antigen Interacts with Cellular Interleukin-1 Receptor Accessory Protein and Triggers Interleukin-1 Response

Chih-Yung Yang,Tzu-Hsing Kuo,Ling-Pai Ting

doi:10.1074/jbc.m510981200

Chih-Yung Yang, Tzu-Hsing Kuo + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m510981200

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Abstract

Human hepatitis B virus (HBV) can cause acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma. HBV e antigen (HBeAg), a secreted protein and not required for viral replication, is thought to play an immunoregulatory role during viral infection. However, the functional involvement of HBeAg in host immune response has not been fully elucidated. We report in this study that HBeAg can bind to interleukin-1 receptor accessory protein (IL-1RAcP). Interleukin-1 (IL-1) plays an important role in inflammation and regulation of immune response, and membrane form of IL-1RAcP (mIL-1RAcP) is an essential component of trimeric IL-1/IL-1 receptor/mIL-1RAcP complex. We show that glutathione S-transferase- or polyhistidine-tagged recombinant HBeAg can interact with endogenous mIL-1RAcP in vitro. Purified (His)6-HBeAg added in the culture medium can interact with overexpressed FLAG-tagged mIL-1RAcP in vivo. Indirect immunofluorescence and confocal microscopy show that HBeAg colocalizes with mIL-1RAcP on the cell surface. Furthermore, HBeAg is able to induce the interaction of IL-1 receptor I (IL-1RI) with mIL-1RAcP and trigger the recruitment of adaptor protein myeloid differentiation factor 88 (MyD88) to the IL-1RI/mIL-1RAcP complex. Assembly and activation of IL-1RI/mIL-1RAcP signaling complex by HBeAg can activate downstream NF-kappaB pathway through IkappaB degradation, induce NF-kappaB-dependent luciferase expression, and induce the expression of IL-1-responsive genes. Silencing of IL-1RAcP by small interfering RNA dramatically abolishes HBeAg-mediated NF-kappaB activation. These results demonstrate that HBeAg can trigger host IL-1 response by binding to mIL-1RAcP. The interaction of HBeAg with mIL-1RAcP may play an important role in modulating host immune response in acute and chronic HBV infection.

Highlights

Patients with persistent hepatitis B virus (HBV) infection are at a high risk of developing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [1, 2]
With regard to hepatocellular carcinogenesis, HBV e antigen (HBeAg)-positive patients have significantly elevated risk of developing HCC [18]. These findings suggest that HBeAg plays an important role in the chronicity and carcinogenesis of HBV infection
In Vivo and in Vitro Interaction between HBeAg and IL-1RAcP—HBeAg shares a large stretch of sequence in common with HBV core protein, which assembles to form viral capsid

Summary

Introduction

Patients with persistent HBV infection are at a high risk of developing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) [1, 2]. The f:mIL-1RAcP protein in the immunoprecipitates and in whole-cell extracts was detected by anti-FLAG antibody. Since the protein sequence encoded by #46 is present in sIL-1RAcP356, the interaction of sIL-1RAcP356 with different core mutants and HBeAg in HEK293T cells was investigated.

Results

Conclusion