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J. Biol. Chem., Vol. 281, Issue 41, 30669-30677, October 13, 2006

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Negative Modulation of RXR Transcriptional Activity by Small Ubiquitin-related Modifier (SUMO) Modification and Its Reversal by SUMO-specific Protease SUSP1^*

Soo Joon Choi¹, Sung Soo Chung¹, Eun Jung Rho, Hyung Woo Lee, Moon Hee Lee, Hueng-Sik Choi, Jae Hong Seol, Sung Hee Baek, Ok Sun Bang², and Chin Ha Chung³

From the National Research Laboratory of Protein Biochemistry, School of Biological Sciences, Seoul National University, Seoul 151-742, Korea and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Korea

Retinoid X receptor (RXR) belongs to a family of ligand-activated transcription factors that regulate many aspects of metazoan life. Here we demonstrate that RXR is a target substrate of a small ubiquitin-related modifier (SUMO)-specific protease, SUSP1, which is capable of controlling the transcriptional activity of RXR. RXR was modified by SUMO-1 in vivo as well as in vitro, and the Lys-108 residue within the IKPP sequence of RXR AF-1 domain was identified as the major SUMO-1 acceptor site. Prevention of SUMO modification by Lys-to-Arg mutation led to an increase not only in the transcriptional activity of RXR but also in the activity of its heterodimeric complex with retinoic acid receptor- or peroxisome proliferator-activated receptor- (PPAR). SUSP1 co-localized with RXR in the nucleus and removed SUMO-1 from RXR but not from androgen receptor or PPAR. Moreover, overexpression of SUSP1 caused an increase in the transcriptional activity of RXR, whereas small hairpin RNA-mediated knockdown of endogenous SUSP1 led to a decrease in RXR activity. These results suggest that SUSP1 plays an important role in the control of the transcriptional activity of RXR and thus in the RXR-mediated cellular processes.

Received for publication, April 27, 2006 , and in revised form, August 14, 2006.

^* This work was supported by grants from the Korea Science and Engineering Foundation (M10533010001-05N3301-00100) and the Korea Research Foundation (KRF-2005-084-C00025). 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 These two authors contributed equally to this work.

² To whom correspondence may be addressed. Tel.: 82-2-880-6693; Fax: 82-2-871-9193; E-mail: osbang{at}snu.ac.kr. ³ To whom correspondence may be addressed. Tel.: 82-2-880-6693; Fax: 82-2-871-9193; E-mail: chchung{at}snu.ac.kr.

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