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Mol. Cell. Biol. 23 (7): 2587-2599

Copyright © 2003 by the American Society for Microbiology. All rights reserved.

Coactivator-Dependent Acetylation Stabilizes Members of the SREBP Family of Transcription Factors

Valeria Giandomenico, Maria Simonsson, Eva Grönroos, and Johan Ericsson*

Ludwig Institute for Cancer Research, S-751 24 Uppsala, Sweden,

Received for publication 2 September 2002. Revision received 21 October 2002. Accepted for publication 7 January 2003.

Abstract: Members of the SREBP family of transcription factors control cholesterol and lipid homeostasis and play important roles during adipocyte differentiation. The transcriptional activity of SREBPs is dependent on the coactivators p300 and CBP. We now present evidence that SREBPs are acetylated by the intrinsic acetyltransferase activity of p300 and CBP. In SREBP1a, the acetylated lysine residue resides in the DNA-binding domain of the protein. Coexpression with p300 dramatically increases the expression of both SREBP1a and SREBP2, and this effect is dependent on the acetyltransferase activity of p300, indicating that acetylation of SREBPs regulates their stability. Indeed, acetylation or mutation of the acetylated lysine residue in SREBP1a stabilizes the protein. We demonstrate that the acetylated residue in SREBP1a is also targeted by ubiquitination and that acetylation inhibits this process. Thus, our studies define acetylation-dependent stabilization of transcription factors as a novel mechanism for coactivators to regulate gene expression.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Box 595, Husargatan 3, S-751 24 Uppsala, Sweden. Phone: 46 18 16 04 05. Fax: 46 18 16 04 20. E-mail: johan.ericsson{at}LICR.uu.se.

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