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Molecular and Cellular Biology, September 2005, p. 7522-7533, Vol. 25, No. 17
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.17.7522-7533.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Activation of Hepatitis B Virus S Promoter by a Cell Type-Restricted IRE1-Dependent Pathway Induced by Endoplasmic Reticulum Stress

Zhi-Ming Huang,¹ Thomas Tan,¹ Hiderou Yoshida,² Kazutoshi Mori,² Yanjun Ma,³ and T. S. Benedict Yen^1,4*

Pathology Service, Veterans Affairs Medical Center, San Francisco, California,¹ Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan,² Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee,³ Department of Pathology, University of California, San Francisco, San Francisco, California⁴

Received 3 November 2004/ Returned for modification 4 February 2005/ Accepted 6 June 2005

IRE1-alpha is an integral membrane protein of the endoplasmic reticulum (ER) that is a key sensor in the cellular transcriptional response to stress in the ER. Upon induction of ER stress, IRE1-alpha is activated, resulting in the synthesis of the active form of the transcription factor XBP1 via IRE1-mediated splicing of its mRNA. In this report, we have examined the role of IRE1-alpha and XBP1 in activation of the hepatitis B virus S promoter by ER stress. Cotransfection experiments revealed that overexpression of either IRE1-alpha or XBP1 activated this promoter. Conversely, cotransfected dominant-negative IRE1-alpha or small interfering RNA directed against XBP1 decreased the activation of the S promoter by ER stress, confirming an important role for the IRE1-alpha/XBP1 signaling pathway in activation of the S promoter. However, XBP1 does not bind directly to the S promoter; rather, a novel S promoter-binding complex that does not contain XBP1 is induced in cells undergoing ER stress in an XBP1-dependent manner. This complex, as well as transcriptional activation of the S promoter, is induced by ER stress in hepatocytes but not in fibroblasts, despite the presence of active XBP1 in the latter. Thus, the hepatitis B virus S promoter responds to a novel, cell type-restricted transcriptional pathway downstream of IRE1-alpha and XBP1.

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* Corresponding author. Mailing address: Pathology Service 113B, VAMC, 4150 Clement Street, San Francisco, CA 94121. Phone: (415) 476-5334. Fax: (415) 750-6947. E-mail: yen{at}itsa.ucsf.edu.

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Molecular and Cellular Biology, September 2005, p. 7522-7533, Vol. 25, No. 17
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.17.7522-7533.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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