The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.
The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.
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DOI：
10.1126/scisignal.aah4117
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发表时间：
2017-01-03
影响因子：
7.3
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Shimizu K;Fukushima H;Ogura K;Lien EC;Nihira NT;Zhang J;North BJ;Guo A;Nagashima K;Nakagawa T;Hoshikawa S;Watahiki A;Okabe K;Yamada A;Toker A;Asara JM;Fukumoto S;Nakayama KI;Nakayama K;Inuzuka H;Wei W
SCFβ-TRCP E3泛素连接酶复合物在正常细胞生理学和病理生理学条件中起关键作用。因此，β-transducin repeat-containing protein（β-TRCP）底物的鉴定对于理解SCFβ-TRCP生物学和功能至关重要。在此，我们在β-TRCP底物筛选中使用了β-TRCP-磷酸降解决定子基序特异性抗体，并结合串联质谱法鉴定了多种β-TRCP底物。这些底物之一是Lipin 1，一种酶和固醇调节元件结合蛋白（SREBP）转录因子家族的抑制因子，其激活编码脂肪生成因子的基因。我们发现SCFβ-TRCP特异性地与Lipin 1相互作用并促进Lipin 1的多聚泛素化，其方式需要通过雷帕霉素1（mTORC 1）和酪蛋白激酶I（CKI）的机制靶点磷酸化Lipin 1。HepG 2肝癌细胞中β-TRCP缺失导致Lipin 1蛋白丰度增加、SREBP依赖性基因表达抑制和甘油三酯合成减弱。此外，β-TRCP 1基因敲除小鼠表现出Lipin 1蛋白丰度增加，并保护其免受高脂饮食诱导的肝脂肪变性。总之，这些数据揭示了β-TRCP在部分通过调节Lipin 1稳定性来调节肝脏脂质代谢稳态中的关键生理功能。
The SCFβ-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of β-transducin repeat-containing protein (β-TRCP) substrates is therefore critical to understand SCFβ-TRCP biology and function. Here, we used a β-TRCP-phosphodegron-motif specific antibody in a β-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple β-TRCP substrates. One of these substrates was Lipin1, an enzyme and suppressor of the family of sterol regulatory element-binding protein (SREBP) transcription factors, which activate genes encoding lipogenic factors. We showed that SCFβ-TRCP specifically interacted with and promoted the polyubiquitination of Lipin1 in a manner that required phosphorylation of Lipin1 by mechanistic target of rapamycin 1 (mTORC1) and casein kinase I (CKI). β-TRCP depletion in HepG2 hepatocellular carcinoma cells resulted in increased Lipin1 protein abundance, suppression of SREBP-dependent gene expression, and attenuation of triglyceride synthesis. Moreover, β-TRCP1 knockout mice showed increased Lipin1 protein abundance and were protected from hepatic steatosis induced by a high-fat diet. Together, these data reveal a critical physiological function of β-TRCP in regulating hepatic lipid metabolic homeostasis in part through modulating Lipin1 stability.
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影响因子：
16
作者：
Gao D;Inuzuka H;Tan MK;Fukushima H;Locasale JW;Liu P;Wan L;Zhai B;Chin YR;Shaik S;Lyssiotis CA;Gygi SP;Toker A;Cantley LC;Asara JM;Harper JW;Wei W
通讯作者：
Wei W
影响因子：
10.5
作者：
Jin, JP;Shirogane, T;Harper, JW
通讯作者：
Harper, JW
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
双重功能脂肪蛋白和甘油代谢。
影响因子：
10.9
作者：
Harris, Thurl E.;Finck, Brian N.
通讯作者：
Finck, Brian N.
影响因子：
50.3
作者：
Inuzuka H;Tseng A;Gao D;Zhai B;Zhang Q;Shaik S;Wan L;Ang XL;Mock C;Yin H;Stommel JM;Gygi S;Lahav G;Asara J;Xiao ZX;Kaelin WG Jr;Harper JW;Wei W
通讯作者：
Wei W