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β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H
- Source :
- Scientific Reports
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
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 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....ae772de0bc57ee5ae4bddb085d7d4574