β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H
| Autor: | Chi-Ping Chan, W Gao, Hei-Man Vincent Tang, Yun Cheng, Dong-Yan Jin, Chi Ming Wong, Jian-Jun Deng |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex Transcription Genetic Beta-Transducin Repeat-Containing Proteins Biology CREB Regulated Intramembrane Proteolysis Article 03 medical and health sciences Ubiquitin Transcription (biology) Humans Amino Acid Sequence Phosphorylation RNA Small Interfering Cyclic AMP Response Element-Binding Protein Transcription factor Binding Sites Multidisciplinary Sequence Homology Amino Acid Ubiquitination Hep G2 Cells beta-Transducin Repeat-Containing Proteins Ubiquitin ligase Protein Transport HEK293 Cells 030104 developmental biology Gene Expression Regulation Liver Biochemistry Proteolysis biology.protein Sequence Alignment Protein Binding Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep23938 |
| Popis: | 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 SCFβ-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. |
| Databáze: | OpenAIRE |
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