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J. Biol. Chem., Vol. 282, Issue 44, 32327-32337, November 2, 2007

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Nucleocytoplasmic Shuttling of the Zinc Finger Protein EZI Is Mediated by Importin-7-dependent Nuclear Import and CRM1-independent Export Mechanisms^*

Eiko Saijou¹, Tohru Itoh¹², Kyung-Woon Kim³, Shun-ichiro Iemura, Tohru Natsume, and Atsushi Miyajima^¶

From the Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, the University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, National Institutes of Advanced Industrial Science and Technology, Biological Information Research Center, Kohtoh-ku, Tokyo 135-0064, Japan, and ^¶Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi-shi, Saitama 332-0012, Japan

Nucleocytoplasmic translocation constitutes a foundation for nuclear proteins to exert their proper functions and hence for various biological reactions to occur normally in eukaryotic cells. We reported previously that EZI/Zfp467, a 12 zinc finger motif-containing protein, localizes predominantly in the nucleus, yet the underlying mechanism still remains elusive. Here we constructed a series of mutant forms of EZI and examined their subcellular localization. The results delineated a non-canonical nuclear localization signal in the region covering the 9th to the 12th zinc fingers, which was necessary for nuclear accumulation of EZI as well as sufficient to confer nuclear localizing ability to a heterologous protein. We also found that the N-terminal domain of EZI is necessary for its nuclear export, the process of which was not sensitive to the CRM1 inhibitor leptomycin B. An interaction proteomics approach and the following co-immunoprecipitation experiments identified the nuclear import receptor importin-7 as a molecule that associated with EZI and, importantly, short interfering RNA-mediated knockdown of importin-7 expression completely abrogated nuclear accumulation of EZI. Taken together, these results identify EZI as a novel cargo protein for importin-7 and demonstrate a nucleocytoplasmic shuttling mechanism that is mediated by importin-7-dependent nuclear localization and CRM1-independent nuclear export.

Received for publication, August 15, 2007

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the CREST program of Japan Science and Technology Agency. 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 Both authors contributed equally to this work.

³ Present address: Molecular and Cellular Glycobiology Unit, Dept. of Biological Science, Sungkyunkwan University, 300 Cheoncheon-Dong, Jangan-gu, Suwon, Gyeonggi-Do 440-746, Korea.

² To whom correspondence should be addressed. Tel.: 81-3-5841-7889; Fax: 81-3-5841-8475; E-mail: itohru{at}iam.u-tokyo.ac.jp.

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