AI Article Synopsis
- The SREBP family of transcription factors plays a key role in regulating cholesterol and lipid metabolism, with their nuclear forms being quickly degraded by the ubiquitin-proteasome pathway.
- A specific phosphodegron in SREBP1a has been identified as a recognition site for the SCF(Fbw7) ubiquitin ligase, which promotes its degradation when certain amino acids are phosphorylated.
- Inhibiting Fbw7 leads to increased stability of SREBP1 and SREBP2, resulting in higher expression of SREBP target genes and increased cholesterol and fatty acid production.
Article 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.
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| http://dx.doi.org/10.1016/j.cmet.2005.04.010 | DOI Listing |
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