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J. Biol. Chem., Vol. 280, Issue 18, 18355-18360, May 6, 2005

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Role of Cyclophilin B in Activation of Interferon Regulatory Factor-3^*

Yoko Obata, Kazuo Yamamoto, Masanobu Miyazaki, Kunitada Shimotohno, Shigeru Kohno, and Toshifumi Matsuyama¶

From the Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523 and the Department of Viral Oncology, Institute for Virus Research, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan

IRF-3 is a member of the interferon regulatory factors (IRFs) and plays a principal role in the induction of interferon- (IFN-) by virus infection. Virus infection results in the phosphorylation of IRF-3 by IB kinase and TANK-binding kinase 1, leading to its dimerization and association with the coactivators CREB-binding protein/p300. The IRF-3 holocomplex translocates to the nucleus, where it induces IFN-. In the present study, we examined the molecular mechanism of IRF-3 activation. Using bacterial two-hybrid screening, we isolated molecules that interact with IRF-3. One of these was cyclophilin B, a member of the immunophilins with a cis-trans peptidyl-prolyl isomerase activity. A GST pull-down assay suggested that one of the autoinhibition domains of IRF-3 and the peptidyl-prolyl isomerase domain of cyclophilin B are required for the binding. A knockdown of cyclophilin B expression by RNA interference resulted in the suppression of virus-induced IRF-3 phosphorylation, leading to the inhibition of the subsequent dimerization, association with CREB-binding protein, binding to the target DNA element, and induction of IFN-. These findings indicate that cyclophilin B plays a critical role in IRF-3 activation.

Received for publication, February 14, 2005

^* This work was supported by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology and by the 21st Century Center of Excellence Program of Nagasaki University. 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. Tel.: 81-95-849-7081; Fax: 81-95-849-7083; E-mail: tosim{at}net.nagasaki-u.ac.jp.

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