Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors

• 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.

Nyckelord

Acetylation

Acetyltransferases/metabolism

Amino Acid Motifs/physiology

Animals

CCAAT-Enhancer-Binding Proteins/*metabolism

COS Cells

Cell Cycle Proteins/metabolism

Cell Line

Cell Nucleus/metabolism

Cyclic AMP Response Element-Binding Protein/metabolism

DNA/metabolism

DNA-Binding Proteins/*metabolism

Gene Expression

Hela Cells

Histone Acetyltransferases

Humans

Multigene Family

Protein Structure; Tertiary/physiology

Recombinant Fusion Proteins/genetics/metabolism

Sterol Regulatory Element Binding Protein 1

Sterol Regulatory Element Binding Protein 2

Sterols/biosynthesis

Transcription Factors/*metabolism

Transfection

Ubiquitin/metabolism

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)