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J. Biol. Chem., Vol. 283, Issue 2, 1018-1025, January 11, 2008

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Physical Interactions and Functional Coupling between Daxx and Sodium Hydrogen Exchanger 1 in Ischemic Cell Death^*

Yong-Sam Jung, Hye-Young Kim¹, Juno Kim, Min-Goo Lee², Jacques Pouysségur^¶, and Eunhee Kim²³

From the School of Bioscience & Biotechnology, Chungnam National University, 220 Gung-dong, Yuseong-gu, Daejeon 305-764, South Korea, the Department of Pharmacology and Brain Korea 21 Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, South Korea, and the ^¶Institute of Signaling, Developmental Biology and Cancer Research, CNRS UMR 6543, University of Nice, Centre A. Lacassagne, 33 Avenue Valombrose, Nice 06189, France

Daxx, a death domain-associated protein, is implicated in ischemic cell death. To clarify the mechanism of cell death mediated by Daxx, a yeast two-hybrid assay was performed. Sodium hydrogen exchanger isoform 1 (NHE1) was identified as a Daxx-interacting protein. During ischemic stress, Daxx translocates from the nucleus to the cytoplasm, where it colocalizes with NHE1. Daxx binds to the ezrin/radixin/moesin-interacting domain of NHE1, in competition with ezrin. Consistent with this finding, transfection of the constitutively cytoplasmic mutant, Daxx(W621A), inhibited ezrin-mediated Akt-1 activation. Moreover, transfection of Daxx(W621A), but not the Daxx(S667A) mutant that is confined to the nucleus, accelerated pH_i recovery from an acid load, indicating that the cytoplasmic protein activates NHE1. Based on the results, we propose that ischemic insult triggers the nucleocytoplasmic translocation of Daxx, following which cytoplasmic Daxx stimulates the NHE1 transporter activity and suppresses activation of the NHE1-ezrin-Akt-1 pathway. Our data support a novel molecular function of Daxx as an upstream regulator of NHE1 in ischemic cell death.

Received for publication, September 14, 2007 , and in revised form, November 12, 2007.

^* This work was supported in part by the Center for Biological Modulators of the 21st Century Frontier R&D Program, MOST, Korea (Grant CBM31-A2300-01-00-00 to E. K.) and by the Korea Health 21 R&D Project, MOHW (Grant 03-PJ10-PG13-GD01-0002 to M. G. L.). 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. S1-S7.

¹ Present address: Solgent Co., Ltd., 63-10 Haam-dong, Yuseong-gu, Daejeon 305-348, South Korea.

² Supported by the Brain Korea 21 project.

³ To whom correspondence should be addressed: Tel.: 82-42-821-5495; Fax: 82-42-821-7542; E-mail: eunhee{at}cnu.ac.kr.

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