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.
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, Cytokine, Ubiquitin, Ubiquitin-Protein Ligases
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, Cytokine, Ubiquitin, Ubiquitin-Protein Ligases
Cell Metab.
Date: Aug. 01, 2007
PubMed ID: 17681147
View in: Pubmed Google Scholar
Download Curated Data For This Publication
86677
Switch View:
- Interactions 8
- PTM Genes 1