A Phosphorylation Cascade Controls the Degradation of Active SREBP1

• Published in: The Journal of biological chemistry 2009-02, Vol.284 (9), p.5885-5895
• Main Authors: Bengoechea-Alonso, Maria T., Ericsson, Johan
• Format: Article
• Language: English
• Subjects: beta-Galactosidase - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; F-Box-WD Repeat-Containing Protein 7; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 - metabolism; HeLa Cells; Humans; Immunoblotting; Immunoprecipitation; Insulin - metabolism; Luciferases - metabolism; MEDICIN; MEDICINE; Phosphorylation; Promoter Regions, Genetic - genetics; Protein Processing, Post-Translational; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M807906200

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.