TY - JOUR
T1 - The SCFβ-TRCP E3 ubiquitin ligase complex targets Lipin1 for ubiquitination and degradation to promote hepatic lipogenesis
AU - Shimizu, Kouhei
AU - Fukushima, Hidefumi
AU - Ogura, Kohei
AU - Lien, Evan C.
AU - Nihira, Naoe Taira
AU - Zhang, Jinfang
AU - North, Brian J.
AU - Guo, Ailan
AU - Nagashima, Katsuyuki
AU - Nakagawa, Tadashi
AU - Hoshikawa, Seira
AU - Watahiki, Asami
AU - Okabe, Koji
AU - Yamada, Aya
AU - Toker, Alex
AU - Asara, John M.
AU - Fukumoto, Satoshi
AU - Nakayama, Keiichi I.
AU - Nakayama, Keiko
AU - Inuzuka, Hiroyuki
AU - Wei, Wenyi
N1 - Funding Information:
W.W. is supported in part by NIH grants (GM094777 and CA177910) and National Natural Science Foundation of China (31528015). W.W. is an American Cancer Society research scholar and a Leukemia and Lymphoma Society research scholar. H.I. was supported by an NIH K01 grant (AG041218), the Charles H. Hood Foundation, and Astellas Foundation for Research on Metabolic Disorders. K.S. was supported by the Naito Foundation and the Uehara Memorial Foundation, and H.F. was supported by a Japan Society for the Promotion of Science Kakenhi grant (26462829). BJ.N. was supported in part by NIH K01 grant AG052627. J.M.A. was supported in part by NIH grants 5P01CA120964, 5P30CA006516, and R35CA197459.
Publisher Copyright:
© 2017 The Authors, some rights reserved.
PY - 2017/1/3
Y1 - 2017/1/3
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.aah4117
DO - 10.1126/scisignal.aah4117
M3 - Article
C2 - 28049764
AN - SCOPUS:85008151977
VL - 10
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1945-0877
IS - 460
ER -