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Article: β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H
Title | β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H |
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Authors | |
Issue Date | 2016 |
Publisher | Nature Publishing Group: Open Access Journals. The Journal's web site is located at http://www.nature.com/srep/index.html |
Citation | Scientific Reports, 2016, v. 6, p. 23938:1-16 How to Cite? |
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. |
Persistent Identifier | http://hdl.handle.net/10722/234400 |
ISSN | 2023 Impact Factor: 3.8 2023 SCImago Journal Rankings: 0.900 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | CHENG, Y | - |
dc.contributor.author | GAO, W | - |
dc.contributor.author | Tang, HMV | - |
dc.contributor.author | Deng, J | - |
dc.contributor.author | Wong, CM | - |
dc.contributor.author | Chan, CP | - |
dc.contributor.author | Jin, D | - |
dc.date.accessioned | 2016-10-14T13:46:37Z | - |
dc.date.available | 2016-10-14T13:46:37Z | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Scientific Reports, 2016, v. 6, p. 23938:1-16 | - |
dc.identifier.issn | 2045-2322 | - |
dc.identifier.uri | http://hdl.handle.net/10722/234400 | - |
dc.description.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. | - |
dc.language | eng | - |
dc.publisher | Nature Publishing Group: Open Access Journals. The Journal's web site is located at http://www.nature.com/srep/index.html | - |
dc.relation.ispartof | Scientific Reports | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.title | β-TrCP-mediated ubiquitination and degradation of liver-enriched transcription factor CREB-H | - |
dc.type | Article | - |
dc.identifier.email | Tang, HMV: tanghmv@hku.hk | - |
dc.identifier.email | Deng, J: dengjj81@hku.hk | - |
dc.identifier.email | Wong, CM: wispwong@hku.hk | - |
dc.identifier.email | Chan, CP: chancp10@hku.hk | - |
dc.identifier.email | Jin, D: dyjin@hku.hk | - |
dc.identifier.authority | Wong, CM=rp01489 | - |
dc.identifier.authority | Chan, CP=rp02031 | - |
dc.identifier.authority | Jin, D=rp00452 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1038/srep23938 | - |
dc.identifier.scopus | eid_2-s2.0-84962781992 | - |
dc.identifier.hkuros | 270236 | - |
dc.identifier.volume | 6 | - |
dc.identifier.spage | 23938:1 | - |
dc.identifier.epage | 16 | - |
dc.identifier.isi | WOS:000373171300002 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 2045-2322 | - |