title: The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis.
abstract: The SCFβ-TRCPE3 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-TRCPbiology 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-TRCPspecifically 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.
authors.affiliation: 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.
authors.forename: Kouhei
authors.identifier: 0000-0001-9523-4296
authors.initials: K
authors.lastname: Shimizu
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.|Department of Infectious Diseases, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Ogura
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Evan C
authors.initials: EC
authors.lastname: Lien
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Naoe Taira
authors.initials: NT
authors.lastname: Nihira
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: North
authors.affiliation: Cell Signaling Technology Inc., Danvers, MA 01923, USA.
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Nagashima
authors.affiliation: Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakagawa
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, 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.
authors.forename: Seira
authors.initials: S
authors.lastname: Hoshikawa
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Asami
authors.initials: A
authors.lastname: Watahiki
authors.affiliation: Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka 814-0193, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Okabe
authors.affiliation: Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Toker
authors.affiliation: Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Division of Cell Regulation Systems, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.affiliation: Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. hinuzuka@bidmc.harvard.edu wwei2@bidmc.harvard.edu.|Center for Advanced Stem Cell and Regenerative Research, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan.
authors.forename: Hiroyuki
authors.identifier: 0000-0002-4892-0047
authors.initials: H
authors.lastname: Inuzuka
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. hinuzuka@bidmc.harvard.edu wwei2@bidmc.harvard.edu.
authors.forename: Wenyi
authors.identifier: 0000-0003-0512-3811
authors.initials: W
authors.lastname: Wei
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010711:Phosphatidate Phosphatase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D059748:Proteolysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D054875:Ubiquitination
chemical_list: D009687:Nuclear Proteins; D044843:SKP Cullin F-Box Protein Ligases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase