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

Yun Cheng, Wei Wei Gao, Hei Man Vincent Tang, Jian Jun Deng, Chi Ming Wong, Chi Ping Chan, Dong Yan Jin

Research output: Journal article publicationJournal articleAcademic researchpeer-review

11 Citations (Scopus)

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-Î "TC, which translocates to the nucleus to activate target gene expression. CREB-H-Î "TC 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-Î "TC. The degradation of CREB-H-Î "TC was mediated by lysine 48-linked polyubiquitination and could be inhibited by proteasome inhibitor. CREB-H-Î "TC 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-Î "TC, whereas knockdown of β-TrCP had the opposite effect. An evolutionarily conserved sequence, SDSGIS, was identified in CREB-H-Î "TC, which functioned as the β-TrCP-binding motif. CREB-H-Î "TC 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.
Original languageEnglish
Article number23938
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 31 Mar 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

Cite this