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Molecular and Cellular Biology, November 2003, p. 7498-7509, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7498-7509.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Modulation of Retinoid Signaling by a Cytoplasmic Viral Protein via Sequestration of Sp110b, a Potent Transcriptional Corepressor of Retinoic Acid Receptor, from the Nucleus

Koichi Watashi,1 Makoto Hijikata,1 Ayako Tagawa,1 Takahiro Doi,1 Hiroyuki Marusawa,2,3 and Kunitada Shimotohno1*

Laboratory of Human Tumor Viruses, Department of Viral Oncology, Institute for Virus Research,1 Division of Gastroenterology and Hepatology, Department of Medicine, Postgraduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan,2 Burnham Institute, La Jolla, California 920373

Received 17 March 2003/ Returned for modification 29 April 2003/ Accepted 24 July 2003

Hepatitis C virus (HCV) core protein (core) plays a significant role in the development of chronic liver diseases caused by HCV infection. We have discovered that the core sensitized all-trans-retinoic acid (ATRA)-induced cell death in MCF-7 cells. Activation of retinoic acid receptor alpha (RAR{alpha})-mediated transcription by the core was also seen in all the cell lines tested. By use of a yeast two-hybrid system, we identified Sp110b as a candidate for a core-interacting cellular factor. Although the function of Sp110b has remained unknown, we observed that Sp110b interacts with RAR{alpha} and suppresses RAR{alpha}-mediated transcription. These data suggest that Sp110b is a transcriptional cofactor negatively regulating RAR{alpha}-mediated transcription. RNA interference-mediated reduction of endogenous Sp110b levels depressed the ability of the core to activate RAR{alpha}-mediated transcription, suggesting an essential role for Sp110b in this pathway. The normal nuclear subcellular localization of Sp110b was altered by molecular interaction with the core to the cytoplasmic surface of the endoplasmic reticulum. This evidence suggests a model in which the core sequesters Sp110b from the nucleus and inactivates its corepressor function to activate RAR{alpha}-mediated transcription. These findings likely describe a novel system in which a cytoplasmic viral protein regulates host cell transcription.

* Corresponding author. Mailing address: Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-4000. Fax: 81-75-751-3998. E-mail: kshimoto{at}virus.kyoto-u.ac.jp.

Molecular and Cellular Biology, November 2003, p. 7498-7509, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7498-7509.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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