Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

doi:10.1073/pnas.0607312104

Critical role of PA28γ in hepatitis C virus-associated steatogenesis and hepatocarcinogenesis

*Department of Molecular Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan;
^†Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;
^‡Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan; and
^§Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved December 1, 2006 (received for review August 23, 2006)

Abstract

Hepatitis C virus (HCV) is a major cause of chronic liver disease that frequently leads to steatosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCV core protein is not only a component of viral particles but also a multifunctional protein because liver steatosis and HCC are developed in HCV core gene-transgenic (CoreTg) mice. Proteasome activator PA28γ/REGγ regulates host and viral proteins such as nuclear hormone receptors and HCV core protein. Here we show that a knockout of the PA28γ gene induces the accumulation of HCV core protein in the nucleus of hepatocytes of CoreTg mice and disrupts development of both hepatic steatosis and HCC. Furthermore, the genes related to fatty acid biosynthesis and srebp-1c promoter activity were up-regulated by HCV core protein in the cell line and the mouse liver in a PA28γ-dependent manner. Heterodimer composed of liver X receptor α (LXRα) and retinoid X receptor α (RXRα) is known to up-regulate srebp-1c promoter activity. Our data also show that HCV core protein enhances the binding of LXRα/RXRα to LXR-response element in the presence but not the absence of PA28γ. These findings suggest that PA28γ plays a crucial role in the development of liver pathology induced by HCV infection.

Footnotes

^¶To whom correspondence should be addressed. E-mail: matsuura{at}biken.osaka-u.ac.jp
Author contributions: K. Moriishi, K.T., T.M., T.S., K.K., and Y. Matsuura designed research; K. Moriishi, R.M., K. Moriya, H.M., Y. Mori, and T.A. performed research; S.M. contributed new reagents/analytic tools; Y. Matsuura analyzed data; and K. Moriishi, K.K., and Y. Matsuura wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0607312104/DC1.
Abbreviations:

CoreTg,

HCV core gene-transgenic;

HCC,

hepatocellular carcinoma;

HCV,

hepatitis C virus;

LXR,

liver X receptor;

LXRE,

liver X receptor-response element;

MEF,

mouse embryonic fibroblast;

ROS,

reactive oxygen species;

RXR,

retinoid X receptor;

SRC-3,

steroid receptor coactivator-3;

SREBP,

steroid regulatory element-binding protein.
Freely available online through the PNAS open access option.