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.
Giandomenico
Valeria
V
Ludwig Institute for Cancer Research, S-751 24 Uppsala, Sweden.
Simonsson
Maria
M
Grönroos
Eva
E
Ericsson
Johan
J
D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism; D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D019556:COS Cells; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015870:Gene Expression; D006367:HeLa Cells; D051548:Histone Acetyltransferases; D006801:Humans; D005810:Multigene Family; D017434:Protein Structure, Tertiary / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols / Q000096:biosynthesis; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor
D000123:Acetyltransferases; D022762:CCAAT-Enhancer-Binding Proteins; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004247:DNA; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D011993:Recombinant Fusion Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D013261:Sterols; D014157:Transcription Factors; D025801:Ubiquitin; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human