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J. Biol. Chem., Vol. 282, Issue 40, 29264-29272, October 5, 2007

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Nucleobindin 1 Controls the Unfolded Protein Response by Inhibiting ATF6 Activation^*

Yoshinori Tsukumo, Akihiro Tomida¹, Osamu Kitahara^¶2, Yusuke Nakamura^¶, Shinichi Asada^||, Kazutoshi Mori^||, and Takashi Tsuruo

From the Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan, the Laboratory of Cell Growth and Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan, the ^¶Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, the ^||Graduate School of Biostudies, Kyoto University, Kyoto 606-8304 Japan

In response to endoplasmic reticulum (ER) stress, activating transcription factor 6 (ATF6), an ER membrane-anchored transcription factor, is transported to the Golgi apparatus and cleaved by site-1 protease (S1P) to activate the unfolded protein response (UPR). Here, we identified nucleobindin 1 (NUCB1) as a novel repressor of the S1P-mediated ATF6 activation. NUCB1 is an ER stress-inducible gene with the promoter region having functional cis-elements for transcriptional activation by ATF6. Overexpression of NUCB1 inhibits S1P-mediated ATF6 cleavage without affecting ER-to-Golgi transport of ATF6, whereas knock-down of NUCB1 by siRNA accelerates ATF6 cleavage during ER stress. NUCB1 protein localizes in the Golgi apparatus, and disruption of the Golgi localization results in loss of the ATF6-inhibitiory activity. Consistent with these observations, NUCB1 can suppress physical interaction of S1P-ATF6 during ER stress. Together, our results demonstrate that NUCB1 is the first-identified, Golgi-localized negative feedback regulator in the ATF6-mediated branch of the UPR.

Received for publication, June 19, 2007 , and in revised form, August 6, 2007.

^* This work was supported in part by a grant-in-aid for scientific research on priority areas for cancer from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. T.) and the Grant-in-Aid for Cancer Research (15-2) from the Ministry of Health, Labour and Welfare and NOVARTIS Foundation (Japan) for the Promotion (to A. T.) and aid from Ishizu Scholarship Foundation (to Y. T.). 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–S5.

² Present address: Pharmacology Research Laboratories II, Pharmaceutical Research Division. Takeda Pharmaceutical Company Limited 10, Wadai, Tsukuba, Ibaraki, 300-4293, Japan.

¹ To whom correspondence should be addressed. Tel.: 81-3-3520-0111(ext. 5405); Fax: 81-3-3570-0484; E-mail: akihiro.tomida{at}jfcr.or.jp.

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