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The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1

Oncogene volume 25, pages 633–642 (2006)Cite this article

Abstract

Hepatitis B virus X protein (HBx) has many cellular functions and is a major factor in hepatitis and hepatocellular carcinoma caused by HBV infection. A proteomic approach was used to search for HBx-interacting proteins in order to elucidate the molecular mechanism of hepatocarcinogenesis. HBx was attached to myc and flag tags (MEF tags) and expressed in 293T cells; the protein complex formed within the cells was purified and characterized by mass spectrometry. COP9 signalosome (CSN) subunits 3 and 4 were subsequently identified as HBx-interacting proteins. In addition, CSN subunit 5, Jun activation domain-binding protein 1 (Jab1), was shown to be a novel cellular target of HBx. In vivo and in vitro interactions between HBx and Jab1 were confirmed by standard immunoprecipitation and GST pull-down assays. An analysis of HBx deletion constructs showed that amino acids 30–125 of HBx were responsible for binding to Jab1. Confocal laser microscopy demonstrated that HBx was mainly localized in the cytoplasm, while Jab1 was found mainly in the nucleus and partially in the cytoplasm, and that the two proteins colocalized in the cytoplasm. The cotransfection of HBx and Jab1 resulted in substantial activator protein 1 (AP-1) activation and knockdown of endogenous Jab1 attenuated AP-1 activation caused by HBx. In addition, the coexpression of HBx and Jab1 potentiated phosphorylation of JNK, leading to the subsequent phosphorylation of c-Jun, whereas the level of c-Jun and JNK phosphorylation induced by HBx was decreased in Jab1 knockdown cells. These results suggest that the interaction between HBx and Jab1 enhances HBx-mediated AP-1 activation.

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Acknowledgements

We thank David J Mann, Michael Karin, Katsuro Koike, Makoto Miyagishi, and Kazunari Taira for providing the plasmids; Tomoki Chiba (Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan) and the members of the Omata lab for helpful discussions; and Mitsuko Tsubouchi for technical assistance. This work was supported in part by the Health Science Research Grants for Medical Frontier Strategy Research from the Ministry of Health, Labor, and Welfare of Japan, and grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. YT is a research fellow of the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Y Tanaka, F Kanai, K Tateishi, Y Asaoka, B Guleng, A Jazag, M Ohta, J Imamura, T Ikenoue, H Ijichi, T Kawabe & M Omata

  2. Clinical Research Center, University of Tokyo Hospital, Tokyo, Japan

    F Kanai & M Omata

  3. Department of Chemistry, Graduate School of Science, Tokyo Metropolitan University, Hachioji-shi, Tokyo, Japan

    T Ichimura & T Isobe

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  1. Y Tanaka
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Correspondence to F Kanai.

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Tanaka, Y., Kanai, F., Ichimura, T. et al. The hepatitis B virus X protein enhances AP-1 activation through interaction with Jab1. Oncogene 25, 633–642 (2006). https://doi.org/10.1038/sj.onc.1209093

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