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Regulated endoplasmic reticulum-associated degradation of a polytopic protein: p97 recruits proteasomes to Insig-1 before extraction from membranes.

Polytopic membrane proteins subjected to endoplasmic reticulum (ER)-associated degradation are extracted from membranes and targeted to proteasomes for destruction. The extraction mechanism is poorly understood. One polytopic ER protein subjected to ER-associated degradation is Insig-1, a negative regulator of cholesterol synthesis. Insig-1 is rapidly degraded by proteasomes when cells are depleted of cholesterol, and its degradation is inhibited when sterols accumulate in cells. Insig-2, a functional homologue of Insig-1, is degraded slowly, and its degradation is not regulated by sterols. Here, we report that a single amino acid substitution in Insig-2, Insig-2(L210A), causes Insig-2 to be degraded in an accelerated and sterol-regulated manner similar to Insig-1. In seeking an explanation for the accelerated degradation, we found that proteasomes bind to wild type Insig-1 and mutant Insig-2(L210A) but not to wild type Insig-2, whereas the proteins are still embedded in cell membranes. This binding depends on at least two factors, ubiquitination of Insig and association with the ATPase p97/VCP complex. These data suggest that p97 recruits proteasomes to polytopic ER proteins even before they are extracted from membranes.

Pubmed ID: 19815544


  • Ikeda Y
  • Demartino GN
  • Brown MS
  • Lee JN
  • Goldstein JL
  • Ye J


The Journal of biological chemistry

Publication Data

December 11, 2009

Associated Grants

  • Agency: NHLBI NIH HHS, Id: 2P01HL20948
  • Agency: NIDDK NIH HHS, Id: R01DK46181

Mesh Terms

  • Adenosine Triphosphatases
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Cell Line
  • Cell Membrane
  • Cholesterol
  • Endoplasmic Reticulum
  • Fatty Acids
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Molecular Sequence Data
  • Nuclear Proteins
  • Proteasome Endopeptidase Complex
  • Protein Subunits
  • RNA Interference
  • Receptors, Autocrine Motility Factor
  • Receptors, Cytokine
  • Sequence Alignment
  • Ubiquitin-Protein Ligases
  • Ubiquitination