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Article: β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H

Titleβ-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H
Authors
Issue Date2016
Citation
Scientific Reports, 2016, v. 6 How to Cite?
AbstractCREB-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.
Persistent Identifierhttp://hdl.handle.net/10722/234400

 

DC FieldValueLanguage
dc.contributor.authorCHENG, Y-
dc.contributor.authorGAO, W-
dc.contributor.authorTang, HMV-
dc.contributor.authorDeng, J-
dc.contributor.authorWong, CM-
dc.contributor.authorChan, CP-
dc.contributor.authorJin, D-
dc.date.accessioned2016-10-14T13:46:37Z-
dc.date.available2016-10-14T13:46:37Z-
dc.date.issued2016-
dc.identifier.citationScientific Reports, 2016, v. 6-
dc.identifier.urihttp://hdl.handle.net/10722/234400-
dc.description.abstractCREB-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.-
dc.languageeng-
dc.relation.ispartofScientific Reports-
dc.titleβ-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H-
dc.typeArticle-
dc.identifier.emailTang, HMV: tanghmv@hku.hk-
dc.identifier.emailDeng, J: dengjj81@hku.hk-
dc.identifier.emailWong, CM: wispwong@hku.hk-
dc.identifier.emailChan, CP: chancp10@hku.hk-
dc.identifier.emailJin, D: dyjin@hku.hk-
dc.identifier.authorityWong, CM=rp01489-
dc.identifier.authorityChan, CP=rp02031-
dc.identifier.authorityJin, D=rp00452-
dc.identifier.doi10.1038/srep23938-
dc.identifier.hkuros270236-
dc.identifier.volume6-

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