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J. Biol. Chem., Vol. 283, Issue 33, 22400-22409, August 15, 2008

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Novel Nuclear Localization Signal Regulated by Ambient Tonicity in Vertebrates^*

Min Seong Kwon, Sang Do Lee¹, Jeong-Ah Kim¹, Emanuela Colla, Yu Jeong Choi, Pann-Ghil Suh, and H. Moo Kwon²

From the Department of Medicine, University of Maryland, Baltimore, Maryland 21201 and the Department of Life Science, Pohang University of Science and Technology, Pohang 790-784, South Korea

TonEBP is a Rel domain-containing transcription factor implicated in adaptive immunity, viral replication, and cancer. In the mammalian kidney, TonEBP is a central regulator of water homeostasis. Animals deficient in TonEBP suffer from life-threatening dehydration due to renal water loss. Ambient tonicity (effective osmolality) is the prominent signal for TonEBP in a bidirectional manner; TonEBP activity decreases in hypotonicity, whereas it increases in hypertonicity. Here we found that TonEBP displayed nuclear export in response to hypotonicity and nuclear import in response to hypertonicity. The nuclear export of TonEBP was not mediated by the nuclear export receptor CRM1 or discrete nuclear export signal. In contrast, a dominant nuclear localization signal (NLS) was found in a small region of 16 amino acid residues. When short peptides containing the NLS were fused to constitutively cytoplasmic proteins, the fusion proteins displayed tonicity-dependent nucleocytoplasmic trafficking like TonEBP. Thus, tonicity-dependent activation of the NLS is crucial in the nucleocytoplasmic trafficking of TonEBP. The novel NLS is present only in the vertebrates, indicating that it developed late in evolution.

Received for publication, December 27, 2007 , and in revised form, May 21, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK61677. 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 Supported by a National Kidney Foundation Fellowship.

² To whom correspondence should be addressed: 22 S. Greene St., Suite N3W143, Baltimore, MD 21201. Fax: 410-706-4314; E-mail: mkwon{at}medicine.umaryland.edu.

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				M. S. Kwon, S. W. Lim, and H. M. Kwon Hypertonic Stress in the Kidney: A Necessary Evil Physiology, June 1, 2009; 24(3): 186 - 191. [Abstract] [Full Text] [PDF]