Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase

Jian Cao, Jiang Wang, Wei Qi, Hong Hua Miao, Jing Wang, Liang Ge, Russell A. DeBose-Boyd, Jing Jie Tang, Bo Liang Li, Bao Liang Song

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

The membrane-anchored ubiquitin ligase gp78 promotes degradation of misfolded endoplasmic reticulum (ER) proteins and sterol-regulated degradation of HMG-CoA reductase. It was known previously that Ufd1 plays a critical role in ER-associated degradation (ERAD) together with Npl4 and VCP. The VCP-Ufd1-Npl4 complex recognizes polyubiquitin chains and transfers the ubiquitinated proteins to the proteasome. Here we show that Ufd1 directly interacts with gp78 and functions as a cofactor. Ufd1 enhances the E3 activity of gp78, accelerates the ubiquitination and degradation of reductase, and eventually promotes receptor-mediated uptake of low-density lipoprotein. Furthermore, we demonstrate that the monoubiquitin-binding site in Ufd1 is required for the enhancement of gp78 activity and that the polyubiquitin-binding site in Ufd1 is critical for a postubiquitination step in ERAD. In summary, our study identifies Ufd1 as a cofactor of gp78, reveals an unappreciated function of Ufd1 in the ubiquitination reaction during ERAD, and illustrates that Ufd1 plays a critical role in cholesterol metabolism.

Original languageEnglish (US)
Pages (from-to)115-128
Number of pages14
JournalCell Metabolism
Volume6
Issue number2
DOIs
StatePublished - Aug 8 2007

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Polyubiquitin
Hydroxymethylglutaryl CoA Reductases
Ubiquitination
Binding Sites
Cholesterol
Endoplasmic Reticulum-Associated Degradation
Ubiquitinated Proteins
Sterols
Proteasome Endopeptidase Complex
Ligases
Ubiquitin
LDL Lipoproteins
Endoplasmic Reticulum
Oxidoreductases
Membranes
Proteins

Keywords

  • HUMDISEASE
  • PROTEINS

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase. / Cao, Jian; Wang, Jiang; Qi, Wei; Miao, Hong Hua; Wang, Jing; Ge, Liang; DeBose-Boyd, Russell A.; Tang, Jing Jie; Li, Bo Liang; Song, Bao Liang.

In: Cell Metabolism, Vol. 6, No. 2, 08.08.2007, p. 115-128.

Research output: Contribution to journalArticle

Cao, Jian ; Wang, Jiang ; Qi, Wei ; Miao, Hong Hua ; Wang, Jing ; Ge, Liang ; DeBose-Boyd, Russell A. ; Tang, Jing Jie ; Li, Bo Liang ; Song, Bao Liang. / Ufd1 Is a Cofactor of gp78 and Plays a Key Role in Cholesterol Metabolism by Regulating the Stability of HMG-CoA Reductase. In: Cell Metabolism. 2007 ; Vol. 6, No. 2. pp. 115-128.
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