A phosphorylation cascade controls the degradation of active SREBP1.
Sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors that regulates cholesterol and lipid metabolism. The active forms of these transcription factors are targeted by a number of post-translational modifications, including phosphorylation. Phosphorylation of Thr-426 and Ser-430 in SREBP1a creates a docking site for the ubiquitin ligase Fbw7, ... resulting in the degradation of the transcription factor. Here, we identify a novel phosphorylation site in SREBP1a, Ser-434, which regulates the Fbw7-dependent degradation of SREBP1. We demonstrate that both SREBP1a and SREBP1c are phosphorylated on this residue (Ser-410 in SREBP1c). Importantly, we demonstrate that the mature form of endogenous SREBP1 is phosphorylated on Ser-434. Glycogen synthase kinase-3 phosphorylates Ser-434, and the phosphorylation of this residue is attenuated in response to insulin signaling. Interestingly, phosphorylation of Ser-434 promotes the glycogen synthase kinase-3-dependent phosphorylation of Thr-426 and Ser-430 and destabilizes SREBP1. Consequently, mutation of Ser-434 blocks the interaction between SREBP1 and Fbw7 and attenuates Fbw7-dependent degradation of SREBP1. Importantly, insulin fails to enhance the levels of mature SREBP1 in cells lacking Fbw7. Thus, the degradation of mature SREBP1 is controlled by cross-talk between multiple phosphorylated residues in its C-terminal domain and the phosphorylation of Ser-434 could function as a molecular switch to control these processes.
Mesh Terms:
Cell Cycle Proteins, F-Box Proteins, Glycogen Synthase Kinase 3, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Insulin, Luciferases, Phosphorylation, Promoter Regions, Genetic, Protein Processing, Post-Translational, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sterol Regulatory Element Binding Protein 1, Ubiquitin-Protein Ligases, Ubiquitination, beta-Galactosidase
Cell Cycle Proteins, F-Box Proteins, Glycogen Synthase Kinase 3, Hela Cells, Humans, Immunoblotting, Immunoprecipitation, Insulin, Luciferases, Phosphorylation, Promoter Regions, Genetic, Protein Processing, Post-Translational, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Sterol Regulatory Element Binding Protein 1, Ubiquitin-Protein Ligases, Ubiquitination, beta-Galactosidase
J. Biol. Chem.
Date: Feb. 27, 2009
PubMed ID: 19126544
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