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

Abstract

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 (RARα)-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 RARα and suppresses RARα-mediated transcription. These data suggest that Sp110b is a transcriptional cofactor negatively regulating RARα-mediated transcription. RNA interference-mediated reduction of endogenous Sp110b levels depressed the ability of the core to activate RARα-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 RARα-mediated transcription. These findings likely describe a novel system in which a cytoplasmic viral protein regulates host cell transcription.

ACKNOWLEDGMENTS

We are grateful to P. Chambon, S. Kato, T. Kiyono, and J. Miyazaki for providing plasmids, M. Kohara for the anti-core antibody, and M. Hosaka for Huh-7 cells carrying an HCV full-genome replicon.

This work was supported by grants-in-aid for cancer research and for the second-term comprehensive 10-year strategy for cancer control from the Ministry of Health, Labor, and Welfare of Japan; by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; by grants-in-aid for research for the future from the Japanese Society for the Promotion of Science; and by the Program for Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (OPSR) of Japan.