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J. Biol. Chem., Vol. 281, Issue 40, 30166-30174, October 6, 2006

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Jab1 Mediates Cytoplasmic Localization and Degradation of West Nile Virus Capsid Protein^*

Wonkyung Oh, Mi-Ran Yang, Eun-Woo Lee, Ki-moon Park, Suhkneung Pyo, Joo-sung Yang^¶, Han-Woong Lee^||, and Jaewhan Song¹

From the Department of Food Science and Biotechnology, the ^¶Department of Genetic Engineering, and the College of Pharmacy, Sungkyunkwan University, Suwon 440-746, and the ^||Department of Biochemistry, Yonsei University, Seoul 120-749, Republic of Korea

The clinical manifestations of West Nile virus (WNV), a member of the Flavivirus family, include febrile illness, sporadic encephalitis, and paralysis. The capsid (Cp) of WNV is thought to participate in these processes by inducing apoptosis through mitochondrial dysfunction and activation of caspase-9 and caspase-3. To further identify the molecular mechanism of the WNV capsid protein (WNVCp), yeast two-hybrid assays were employed using WNV-Cp as bait. Jab1, the fifth subunit of the COP9 signalosome, was subsequently identified as a molecule that interacts with WNVCp. Immunoprecipitation and glutathione S-transferase pulldown assays confirmed that direct interaction could occur between WNVCp and Jab1. Immunofluorescence microscopy demonstrated that the overexpressed WNVCp, which localized to the nucleolus, was translocated to the cytoplasm upon its co-expression with Jab1. When treated with leptomycin B, Jab1-facilitated nuclear exclusion of WNVCp was prevented, which indicated that the CRM1 complex is required for Jab1-facilitated nuclear export of WNVCp. Moreover, Jab1 promoted the degradation of WNVCp in a proteasome-dependent way. Consistent with this, WNVCp-mediated cell cycle arrest at the G₂ phase in H1299 was prevented by exogenous Jab1. Finally, an analysis of WNVCp deletion mutants indicated that the first 15 amino acids were required for interaction with Jab1. Furthermore, the double-point mutant of the WNVCp, P5A/P8A, was incapable of binding to Jab1. These results indicate that Jab1 has a potential protective effect against pathogenic WNVCp and might provide a novel target site for the treatment of disease caused by WNV.

Received for publication, March 21, 2006 , and in revised form, July 25, 2006.

^* This work was supported by Grants R01-2002-000-00445-0 from the Korea Science and Engineering Foundation, SeokChon Project 2002-0706-000 from Sungkyunkwan University, 21C Frontier Functional Human Genome Project FG05-22-02, and Brain Research Center Frontier M103KV 010018-05K2201-01830 from the Ministry of Science and Technology, Republic of Korea. 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.

¹ To whom correspondence should be addressed: Dept. of Food Science and Biotechnology, Faculty of Life Science and Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Tel.: 82-31-290-7807; Fax: 82-31-299-6435; E-mail: jso678{at}skku.edu.

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