The SCF_β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.

Kouhei Shimizu; Hidefumi Fukushima; Kohei Ogura; Lien, Evan C.; Nihira, Naoe Taira; Jinfang Zhang; North, Brian J.; Guo, Ailan; Katsuyuki Nagashima; Tadashi Nakagawa; Seira Hoshikawa; Asami Watahiki; Koji Okabe; Aya Yamada; Toker, Alex; Asara, John M.; Fukumoto, Satoshi; Nakayama, Keiichi I.; Nakayama, Keiko; Hiroyuki Inuzuka

The SCFβ-TRCP E3 ubiquitin ligase complex plays pivotal roles in normal cellular physiology and in pathophysiological conditions. Identification of b-transducin repeat-containing protein (β-TRCP) substrates is therefore critical to understand SCFβ-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 SCFβ-TRCP specifically interacted with and promoted the polyubiquitination of Lipin1 in amanner 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 lipidmetabolic homeostasis in part throughmodulating Lipin1 stability.

UBIQUITINATION; LIPID synthesis; STEROL regulatory element-binding proteins; CASEIN kinase; PHOSPHORYLATION

Science Signaling, 2017, Vol 10, Issue 460, p1

1945-0877

Academic Journal

10.1126/scisignal.aah4117