Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCFFbw7
Control of lipid metabolism by phosphorylation-dependent degradation of the SREBP family of transcription factors by SCFFbw7
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DOI：
10.1016/j.cmet.2005.04.010
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发表时间：
2005-06-01
期刊：
影响因子：
29
通讯作者：
Ericsson, J
中科院分区：
文献类型：
--
作者：
Sundqvist, A;Bengoechea-Alonso, MT;Ericsson, J
固醇调节元件结合蛋白（SREBP）家族的转录因子控制胆固醇和脂质代谢。这些蛋白质的核形式通过泛素-蛋白酶体途径迅速降解，但所需的信号和因子尚不清楚。在这里，我们确定了一个磷酸降解决定子在SREBP 1a，作为识别基序的SCFFbw 7泛素连接酶。Fbw 7与核SREBP 1a相互作用，并以依赖于GSK-3对T426和S430的磷酸化的方式增强其泛素化和降解。Fbw 7还降解核SREBP 1c和SREBP 2，内源性Fbw 7的失活导致核SREBP 1和-2的稳定，SREBP靶基因的表达增强，胆固醇和脂肪酸的合成增强，以及受体介导的LDL摄取增强。因此，我们的研究结果表明，Fbw 7可能是一个主要的调节脂质代谢，通过控制磷酸化依赖性降解的SREBP家族的转录因子。
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 SCFFbw7 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.