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MBC in Press, published online ahead of print January 4, 2006
Mol. Biol. Cell 10.1091/mbc.E05-09-0853

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Submitted on September 12, 2005
Revised on November 29, 2005
Accepted on December 27, 2005

Hsp90 Regulates Activation of IRF-3 and TBK-1 Stabilization in Sendai Virus-infected Cells

Kai Yang, Hexin Shi, Rong Qi, Shaogang Sun, Yujie Tang, Bianhong Zhang, and Chen Wang

Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People’s Republic of China

Monitoring Editor: Carl-Henrik Heldin

Interferon regulatory factor 3 (IRF3) plays a crucial role in mediating cellular responses to virus intrusion. The protein kinase TBK1 is a key regulator inducing phosphorylation of IRF3. The regulatory mechanisms during IRF3 activation remain poorly characterized. In the present study, we have identified by yeast two hybrid approach a specific interaction between IRF3 and chaperone Hsp90. C-terminal truncation mutant of Hsp90 is a strong dominant-negative inhibitor of IRF3 activation. Knockdown of endogenous Hsp90 by RNA interference attenuates IRF3 activation and its target gene expressions. Alternatively, Hsp90 specific inhibitor Geldanamycin (GA) dramatically reduces expression of IRF3-regulated ISGs and abolishes the cytoplasm-to-nucleus translocation and DNA binding activity of IRF3 in Sendai virus-infected cells. Significantly, virus-induced IRF3 phosphorylation is blocked by GA, while GA does not affect the protein level of IRF3. In addition, TBK1 is found to be a client protein of Hsp90 in vivo. Treatment of 293 cells with GA interferes with the interaction of TBK1 and Hsp90, resulting in TBK1 destabilization and its subsequent proteasome-mediated degradation. Besides maintaining stability of TBK1, Hsp90 also forms a novel complex with TBK1 and IRF3, which brings TBK1 and IRF3 dynamically into close proximity and facilitates signal transduction from TBK1 to IRF3. Our study uncovers an essential role of Hsp90 in the virus-induced activation of IRF3.

Address correspondence to: Chen Wang (cwang01{at}sibs.ac.cn)




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