Unsaturated fatty acids inhibit proteasomal degradation of Insig-1 at a postubiquitination step.

Proteasomes mediate the regulated degradation of Insig-1, a membrane protein of the endoplasmic reticulum (ER) that plays a crucial role in lipid metabolism. We showed previously that sterols inhibit this degradation by blocking ubiquitination of Insig-1. Here we show that unsaturated fatty acids stabilize Insig-1 without affecting its ubiquitination. Instead ...
unsaturated fatty acids inhibit extraction of ubiquitinated Insig-1 from membranes, a process known to be mediated by valosin-containing protein and necessary for ER-associated degradation. Valosin-containing protein is recruited to Insig-1 through the action of another protein, Ubxd8. Unsaturated fatty acids block the binding between Ubxd8 and Insig-1, thereby abrogating the membrane extraction of Insig-1. Unsaturated fatty acid-mediated stabilization of Insig-1 enhances the ability of sterols to inhibit proteolytic activation of SREBP-1, which activates transcription of genes involved in fatty acid synthesis. The current study provides a molecular mechanism for regulation of proteasome-mediated ER protein degradation at a postubiquitination step.
Mesh Terms:
Adenosine Triphosphatases, Animals, CHO Cells, Carrier Proteins, Cell Cycle Proteins, Cricetinae, Cricetulus, Endoplasmic Reticulum, Fatty Acids, Unsaturated, Humans, Intracellular Membranes, Intracellular Signaling Peptides and Proteins, Lipid Metabolism, Membrane Proteins, Proteasome Endopeptidase Complex, Sterol Regulatory Element Binding Protein 1, Transcription, Genetic, Ubiquitination
J. Biol. Chem.
Date: Nov. 28, 2008
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