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Membrane-associated ubiquitin ligase complex containing gp78 mediates sterol-accelerated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

The endoplasmic reticulum (ER)-associated degradation (ERAD) pathway in the yeast Saccharomyces cerevisiae is mediated by two membrane-bound ubiquitin ligases, Doa10 and Hrd1. These enzymes are found in distinct multiprotein complexes that allow them to recognize and target a variety of substrates for proteasomal degradation. Although multiprotein complexes containing mammalian ERAD ubiquitin ligases likely exist, they have yet to be identified and characterized in detail. Here, we identify two ER membrane proteins, SPFH2 and TMUB1, as associated proteins of mammalian gp78, a membrane-bound ubiquitin ligase that bears significant sequence homology with mammalian Hrd1 and mediates sterol-accelerated ERAD of the cholesterol biosynthetic enzyme HMG-CoA reductase. Co-immunoprecipitation studies indicate that TMUB1 bridges SPFH2 to gp78 in ER membranes. The functional significance of these interactions is revealed by the observation that RNA interference (RNAi)-mediated knockdown of SPFH2 and TMUB1 blunts both the sterol-induced ubiquitination and degradation of endogenous reductase in HEK-293 cells. These studies mark the initial steps in the characterization of the mammalian gp78 ubiquitin ligase complex, the further elucidation of which may yield important insights into mechanisms underlying gp78-mediated ERAD.

Pubmed ID: 21343306 RIS Download

Mesh terms: Carrier Proteins | Cell Line | Endoplasmic Reticulum | Humans | Hydroxymethylglutaryl CoA Reductases | Ligases | Membrane Proteins | Multiprotein Complexes | Nuclear Proteins | Protein Stability | Receptors, Autocrine Motility Factor | Receptors, Cytokine | Sterols | Ubiquitin-Protein Ligases

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Associated grants

  • Agency: NHLBI NIH HHS, Id: P01 HL020948
  • Agency: NHLBI NIH HHS, Id: HL20948
  • Agency: NIGMS NIH HHS, Id: R01 GM090216
  • Agency: Howard Hughes Medical Institute, Id: GM090216
  • Agency: NIGMS NIH HHS, Id:

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