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- Title
The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.
- Authors
Shimizu, Kouhei; Fukushima, Hidefumi; Ogura, Kohei; Lien, Evan C; Nihira, Naoe Taira; Zhang, Jinfang; North, Brian J; Guo, Ailan; Nagashima, Katsuyuki; Nakagawa, Tadashi; Hoshikawa, Seira; Watahiki, Asami; Okabe, Koji; Yamada, Aya; Toker, Alex; Asara, John M; Fukumoto, Satoshi; Nakayama, Keiichi I; Nakayama, Keiko; Inuzuka, Hiroyuki; Wei, Wenyi
- Abstract
The SCF β-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 SCF β-TRCP biology and function. 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 SCF β-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.
- Publication
Science signaling, 2017, Vol 10, Issue 460
- ISSN
1937-9145
- Publication type
Journal Article
- DOI
10.1126/scisignal.aah4117