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J. Biol. Chem., Vol. 282, Issue 8, 5888-5898, February 23, 2007

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Reticulon 3 Binds the 2C Protein of Enterovirus 71 and Is Required for Viral Replication^*

Wen-Fang Tang, Shing-Ying Yang, Bin-Wen Wu, Jia-Rong Jheng, Yin-Li Chen, Chung-Hsuan Shih, Kwang-Huei Lin, Hsin-Chi Lai, Petrus Tang^¶, and Jim-Tong Horng^¶1

From the Department of Biochemistry and ^¶Chang Gung Bioinformatics Center, Chang Gung University, Kweishan, Taoyuan 333, Taiwan and the Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei 106, Taiwan

Enterovirus 71 is an enterovirus of the family Picornaviridae. The 2C protein of poliovirus, a relative of enterovirus 71, is essential for viral replication. The poliovirus 2C protein is associated with host membrane vesicles, which form viral replication complexes where viral RNA synthesis takes place. We have now identified a host-encoded 2C binding protein called reticulon 3, which we found to be associated with the replication complex through direct interaction with the enterovirus 71-encoded 2C protein. We observed that the N terminus of the 2C protein, which has both RNA- and membrane-binding activity, interacted with reticulon 3. This region of interaction was mapped to its reticulon homology domain, whereas that of 2C was encoded by the 25th amino acid, isoleucine. Reticulon 3 could also interact with the 2C proteins encoded by other enteroviruses, such as poliovirus and coxsackievirus A16, implying that it is a common factor for such viral replication. Reduced production of reticulon 3 by RNA interference markedly reduced the synthesis of enterovirus 71-encoded viral proteins and replicative double-stranded RNA, reducing plaque formation and apoptosis. Furthermore, reintroduction of nondegradable reticulon 3 into these knockdown cells rescued enterovirus 71 infectivity, and viral protein and double-stranded RNA synthesis. Thus, reticulon 3 is an important component of enterovirus 71 replication, through its potential role in modulation of the sequential interactions between enterovirus 71 viral RNA and the replication complex.

Received for publication, December 5, 2006

^* This work was supported by grants from the National Science Council of Taiwan Grant (NSC 95-2311-B-182-007-MY3) and from Chang Gung University and Memorial Hospital, Taiwan (CMRP32028 and 33010). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Associated with the Emerging Viral Infection Research Center, Chang Gung University. To whom correspondence should be addressed: Dept. of Biochemistry, Chang Gung University, 259 Wen-Hwa First Rd., Kweishan, Taoyuan 333, Taiwan. Tel./Fax: 886-3-2118407; E-mail: jimtong{at}mail.cgu.edu.tw.

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