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Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase.

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.

Pubmed ID: 17681147

Authors

  • Cao J
  • Wang J
  • Qi W
  • Miao HH
  • Wang J
  • Ge L
  • DeBose-Boyd RA
  • Tang JJ
  • Li BL
  • Song BL

Journal

Cell metabolism

Publication Data

August 7, 2007

Associated Grants

None

Mesh Terms

  • Amino Acids
  • Animals
  • Binding Sites
  • CHO Cells
  • Cell Line
  • Cholesterol
  • Cricetinae
  • Cricetulus
  • Enzyme Stability
  • Humans
  • Hydroxymethylglutaryl CoA Reductases
  • Lipoproteins, LDL
  • Models, Biological
  • Protein Binding
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Proteins
  • Receptors, Autocrine Motility Factor
  • Receptors, Cytokine
  • Ubiquitin
  • Ubiquitin-Protein Ligases