Phosphorylation and ubiquitination of the transcription factor sterol regulatory element-binding protein-1 in response to DNA binding.
Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors control cholesterol and lipid metabolism and play critical roles during adipocyte differentiation. The transcription factor SREBP1 is degraded by the ubiquitin-proteasome system following phosphorylation of Thr426 and Ser430 in its phosphodegron. We now demonstrate that the glycogen synthase kinase (GSK)-3beta-dependent phosphorylation of these residues in SREBP1 is enhanced in response to specific DNA binding. DNA binding enhances the direct interaction between the C-terminal domain of SREBP1 and GSK-3beta. Accordingly, we demonstrate that GSK-3beta is recruited to the promoters of SREBP target genes in vivo. As a result of the phosphorylation of Thr426 and Ser430, the ubiquitin ligase Fbw7 is recruited to SREBP molecules associated with target promoters. Using a reconstituted ubiquitination system, we demonstrate that Fbw7-mediated ubiquitination of SREBP1 is dependent on its DNA binding activity. Thus, DNA binding could provide a mechanistic link between the phosphorylation, ubiquitination, and degradation of active transcription factors.
Punga
Tanel
T
Ludwig Institute for Cancer Research, Uppsala University, Biomedical Center, Husargatan 3, S-751 24 Uppsala, Sweden.
Bengoechea-Alonso
Maria T
MT
Ericsson
Johan
J
D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006367:HeLa Cells; D006801:Humans; D050356:Lipid Metabolism; D009154:Mutation; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D051780:Sterol Regulatory Element Binding Protein 1 / Q000737:chemistry*; D025801:Ubiquitin / Q000737:chemistry*
C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D025801:Ubiquitin; D004247:DNA; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex