期刊
SCIENCE SIGNALING
卷 10, 期 460, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aah4117
关键词
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资金
- NIH [GM094777, CA177910, 5P01CA120964, 5P30CA006516, R35CA197459]
- National Natural Science Foundation of China [31528015]
- NIH K01 grant [AG041218, AG052627]
- Charles H. Hood Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Naito Foundation
- Uehara Memorial Foundation
- Japan Society for the Promotion of Science Kakenhi grant [26462829]
- Grants-in-Aid for Scientific Research [15K18977, 16H05529, 26462829, 17K10432, 16H05548] Funding Source: KAKEN
The SCF beta-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of beta-transducin repeat-containing protein (beta-TRCP) substrates is therefore critical to understand SCF beta-TRCP biology and function. We used a beta-TRCP-phosphodegron motif-specific antibody in a beta-TRCP substrate screen coupled with tandem mass spectrometry and identified multiple b-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 SCF beta-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). beta-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, beta-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 beta-TRCP in regulating hepatic lipidmetabolic homeostasis in part through modulating Lipin1 stability.
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