title: Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCF(Fbw7).
abstract: The sterol regulatory element binding protein (SREBP) family of transcription factors controls cholesterol and lipid metabolism. The nuclear forms of these proteins are rapidly degraded by the ubiquitin-proteasome pathway, but the signals and factors required for this are unknown. Here, we identify a phosphodegron in SREBP1a that serves as a recognition motif for the SCF(Fbw7) ubiquitin ligase. Fbw7 interacts with nuclear SREBP1a and enhances its ubiquitination and degradation in a manner dependent on the phosphorylation of T426 and S430 by GSK-3. Fbw7 also degrades nuclear SREBP1c and SREBP2, and inactivation of endogenous Fbw7 results in stabilization of nuclear SREBP1 and -2, enhanced expression of SREBP target genes, enhanced synthesis of cholesterol and fatty acids, and enhanced receptor-mediated uptake of LDL. Thus, our results suggest that Fbw7 may be a major regulator of lipid metabolism through control of the phosphorylation-dependent degradation of the SREBP family of transcription factors.
authors.affiliation: Ludwig Institute for Cancer Research, Box 595, Husargatan 3, S-751 24 Uppsala, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Sundqvist
authors.forename: Maria T
authors.initials: MT
authors.lastname: Bengoechea-Alonso
authors.forename: Xin
authors.initials: X
authors.lastname: Ye
authors.forename: Vasyl
authors.initials: V
authors.lastname: Lukiyanchuk
authors.forename: Jianping
authors.initials: J
authors.lastname: Jin
authors.forename: J Wade
authors.initials: JW
authors.lastname: Harper
authors.forename: Johan
authors.initials: J
authors.lastname: Ericsson
mesh_terms: D020816:Amino Acid Motifs; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D005810:Multigene Family; D010766:Phosphorylation; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D025801:Ubiquitin; D044843:SKP Cullin F-Box Protein Ligases; D038362:Glycogen Synthase Kinase 3