title: β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H.
abstract: CREB-H is an endoplasmic reticulum-resident bZIP transcription factor which critically regulates lipid homeostasis and gluconeogenesis in the liver. CREB-H is proteolytically activated by regulated intramembrane proteolysis to generate a C-terminally truncated form known as CREB-H-ΔTC, which translocates to the nucleus to activate target gene expression. CREB-H-ΔTC is a fast turnover protein but the mechanism governing its destruction was not well understood. In this study, we report on β-TrCP-dependent ubiquitination and proteasomal degradation of CREB-H-ΔTC. The degradation of CREB-H-ΔTC was mediated by lysine 48-linked polyubiquitination and could be inhibited by proteasome inhibitor. CREB-H-ΔTC physically interacted with β-TrCP, a substrate recognition subunit of the SCF(β-TrCP) E3 ubiquitin ligase. Forced expression of β-TrCP increased the polyubiquitination and decreased the stability of CREB-H-ΔTC, whereas knockdown of β-TrCP had the opposite effect. An evolutionarily conserved sequence, SDSGIS, was identified in CREB-H-ΔTC, which functioned as the β-TrCP-binding motif. CREB-H-ΔTC lacking this motif was stabilized and resistant to β-TrCP-induced polyubiquitination. This motif was a phosphodegron and its phosphorylation was required for β-TrCP recognition. Furthermore, two inhibitory phosphorylation sites close to the phosphodegron were identified. Taken together, our work revealed a new intracellular signaling pathway that controls ubiquitination and degradation of the active form of CREB-H transcription factor.
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Yun
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Gao
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.
authors.forename: Hei-Man Vincent
authors.initials: HM
authors.lastname: Tang
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.|Department of Food Science and Engineering, College of Chemical Engineering, Northwestern University, Xi'an 710069, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Deng
authors.affiliation: Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.|Department of Medicine and State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chi-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.
authors.forename: Chi-Ping
authors.initials: CP
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Pokfulam, Hong Kong.|Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D054875:Ubiquitination; D044844:beta-Transducin Repeat-Containing Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: C533813:CREB3L3 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D034741:RNA, Small Interfering; D044844:beta-Transducin Repeat-Containing Proteins; D046988:Proteasome Endopeptidase Complex