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.
Lee
Joon No
JN
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Zhang
Xiangyu
X
Feramisco
Jamison D
JD
Gong
Yi
Y
Ye
Jin
J
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D054875:Ubiquitination / Q000502:physiology*; D000074405:Valosin Containing Protein
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D005231:Fatty Acids, Unsaturated; C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein