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J. Biol. Chem., Vol. 280, Issue 13, 12246-12254, April 1, 2005

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Repression and Coactivation of CCAAT/Enhancer-binding Protein by Sumoylation and Protein Inhibitor of Activated STATx Proteins^*

Jinyong Kim, Savitha Sharma, Yamin Li, Everardo Cobos¶, Jorma J. Palvimo||, and Simon C. Williams¶**

From the Department of Cell Biology and Biochemistry and Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, the ^||Department of Medical Biochemistry, University of Kuopio, Kuopio, Finland, and the ^¶Southwest Cancer Center at University Medical Center, Lubbock, Texas 79430

CCAAT/enhancer-binding protein (C/EBP) is a neutrophil-specific transcription factor whose activity is controlled by juxtaposed activating and regulatory domains. We previously determined that the function of the major regulatory domain (RD1) in C/EBP was dependent on the integrity of a five-amino acid motif that was identical to the recognition site for members of the small ubiquitin-like modifier (SUMO) family of ubiquitin-related proteins. We show here that the SUMO attachment site (the regulatory domain motif) is necessary and sufficient both for the intrinsic inhibitory function of RD1 and for coactivation by PIASx and PIASx, two members of the protein inhibitor of activated STAT (PIAS) family of SUMO E3 ligases. PIASx was a more potent coactivator than PIASx of both full-length C/EBP and fusion proteins containing the N-terminal portion of C/EBP, whereas PIASx was more active on fusion proteins containing a heterologous activation domain. Two modes of coactivation were observed, one that was dependent on the integrity of the RING finger (RF) domain and was shared by both PIASx and PIASx and a second mode that was independent of the RF and was only observed with PIASx. Sumoylation of C/EBP was enhanced by coexpression of PIASx, suggesting that this modification is associated with the enhanced activity of the target protein. These results suggest that a complex interplay of accessory factors, including SUMO and PIAS proteins, modulates the activity of C/EBP.

Received for publication, December 7, 2004 , and in revised form, January 18, 2005.

^* This work was supported by an Established Investigator Award from the American Heart Association and grants from the CH Foundation, South Plains Foundation, and SouthWest Cancer Center at UMC (to S. C. W.). 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.

^** To whom correspondence should be addressed: Dept. of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th St., Lubbock, TX 79430. Tel.: 806-743-2524; Fax: 806-743-2990; E-mail: simon.williams{at}ttuhsc.edu.

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