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.
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, Cytokine, Sequence Alignment, Ubiquitin-Protein Ligases, Ubiquitination
J. Biol. Chem.
Date: Dec. 11, 2009
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