The SCF β-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis
Authors: Kohei Ogura
Koji Okabe
Evan C Lien
Kouhei Shimizu
Asami Watahiki
Hiroyuki Inuzuka
Satoshi Fukumoto
Brian J North
Jinfang Zhang
Katsuyuki Nagashima
John M Asara
Seira Hoshikawa
Keiichi I Nakayama
Alex Toker
Tadashi Nakagawa
Wenyi Wei
Hidefumi Fukushima
Keiko Nakayama
Aya Yamada
Ailan Guo
Naoe Taira Nihira
Journal: Science Signaling (2017)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: SCFβ-TRCP; E3 ubiquitin ligase; β-TRCP substrates; Lipin1; SREBP transcription factors
Affiliations: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan., Department of Infectious Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan., Cell Signaling Technology Inc., Danvers, MA 01923, USA., Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan., Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan., Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan., Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan., Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.  .

Abstract:  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. 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. 

Retracted: No

PubPeer comments:
 The authors conducted a sensitivity analysis on the criterion weights and claimed that u201c**All indicators have 30%, 20% and 10% less weight than the baseline weight and 10%, 20% and 30% more weight than the baseline weight, and the results are shown in Fig. 9.**u201d There are five weights in this numerical example which are constrained by the normalization condition $$w_1 + w_2 + w_3 +w_4 + w_5 =1$$ The information demonstrated in Fig. 9 implies that exactly one of the weight values is changed while others are fixed. This is confusing because under the normalization constraint **there is no way to change one of the values while keeping others unchanged.** Can the authors kindly explain how this sensitivity analysis was conducted? ![file] ![file] ,