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Originally published In Press as doi:10.1074/jbc.M312144200 on February 11, 2004
J. Biol. Chem., Vol. 279, Issue 17, 17158-17164, April 23, 2004
Hepatitis C Virus Suppresses the IRE1-XBP1 Pathway of the Unfolded Protein Response*
Keith D. Tardif ,
Kazutoshi Mori ,
Randal J. Kaufman¶, and
Aleem Siddiqui||
From the
Department of Microbiology and Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado 80262, the Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan, and the ¶Howard Hughes Medical Institute and Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109
Hepatitis C virus (HCV) gene expression disrupts normal endoplasmic reticulum (ER) functions and induces ER stress. ER stress results from the accumulation of unfolded or misfolded proteins in the ER; cells can alleviate this stress by degrading or refolding these proteins. The IRE1-XBP1 pathway directs both protein refolding and degradation in response to ER stress. Like IRE1-XBP1, other branches of the ER stress response mediate protein refolding. However, IRE1-XBP1 can also specifically activate protein degradation. We show here that XBP1 expression is elevated in cells carrying HCV subgenomic replicons, but XBP1 trans-activating activity is repressed. This prevents the IRE1-XBP1 transcriptional induction of EDEM (ER degradation-enhancing  -mannosidase-like protein). The mRNA expression of EDEM is required for the degradation of misfolded proteins. Consequently, misfolded proteins are stable in cells expressing HCV replicons. HCV may suppress the IRE1-XBP1 pathway to stimulate the synthesis of its viral proteins. IRE1-null MEFs, a cell line with a defective IRE1-XBP1 pathway, show elevated levels of HCV IRES-mediated translation. Therefore, HCV may suppress the IRE1-XBP1 pathway to not only promote HCV expression but also to contribute to the persistence of the virus in infected hepatocytes.
Received for publication, November 5, 2003
, and in revised form, February 6, 2004.
* This work was supported by a Postdoctoral Training Grant T3-DK07038 from National Institutes of Health (to K. D. T.), National Institutes of Health Grant DK061566 (to A. S.), and Grant 15GS0310 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to K. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
|| To whom correspondence should be addressed: University of Colorado Health Sciences Center, Dept. of Microbiology, Campus Box B-172, 4200 East 9th Ave, Denver, CO 80262. Tel.: 303-315-7016; Fax: 303-315-8330; E-mail: Aleem.Siddiqui{at}UCHSC.edu.
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Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
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