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Sterol-induced degradation of HMG CoA reductase depends on interplay of two Insigs and two ubiquitin ligases, gp78 and Trc8.

http://www.ncbi.nlm.nih.gov/pubmed/22143767

Accumulation of sterols in membranes of the endoplasmic reticulum (ER) leads to the accelerated ubiquitination and proteasomal degradation of 3-hydroxy-3-methylglutaryl coenzyme A reductase, a rate-limiting enzyme in synthesis of cholesterol and nonsterol isoprenoids. This degradation results from sterol-induced binding of reductase to the Insig-1 or Insig-2 proteins of ER membranes. We previously reported that in immortalized human fibroblasts (SV-589 cells) Insig-1, but not Insig-2, recruits gp78, a membrane-bound RING-finger ubiquitin ligase. We now report that both Insig-1 and Insig-2 bind another membrane-bound RING-finger ubiquitin ligase called Trc8. Knockdown of either gp78 or Trc8 in SV-589 cells through RNA interference (RNAi) inhibited sterol-induced ubiquitination of reductase and inhibited sterol-induced degradation by 50-60%. The combined knockdown of gp78 and Trc8 produced a more complete inhibition of degradation (> 90%). Knockdown of gp78 led to a three to fourfold increase in levels of Trc8 and Insig-1 proteins, which opposed the inhibitory action of gp78. In contrast, knockdown of Trc8 had no effect on gp78 or Insig-1. The current results suggest that sterol-induced ubiquitination and proteasomal degradation of reductase is dictated by the complex interplay of at least four proteins: Insig-1, Insig-2, gp78, and Trc8. Variations in the concentrations of any one of these proteins may account for differences in cell- and/or tissue-specific regulation of reductase degradation.

Pubmed ID: 22143767 RIS Download

Mesh terms: Animals | CHO Cells | Cricetinae | Cricetulus | Endoplasmic Reticulum | Fibroblasts | Hydroxymethylglutaryl CoA Reductases | Intracellular Signaling Peptides and Proteins | Membrane Proteins | RNA Interference | Receptors, Autocrine Motility Factor | Receptors, Cell Surface | Sterols | Ubiquitin-Protein Ligases

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Associated grants

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

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