Sterol-regulated degradation of Insig-1 mediated by the membrane-bound ubiquitin ligase gp78.
Insig-1 and Insig-2, closely related endoplasmic reticulum membrane proteins, mediate transcriptional and post-transcriptional mechanisms that assure cholesterol homeostasis through their sterol-induced binding to Scap (SREBP cleavage-activating protein) and 3-hydroxy-3-methylglutaryl coenzyme A reductase. Recent studies show that Insig-1 (but not Insig-2) is ubiquitinated and rapidly degraded when cells are depleted of sterols. Conversely, ubiquitination of Insig-1 is blocked, and the protein is stabilized when intracellular sterols accumulate. Here, we report that the ubiquitin ligase gp78, which binds with much higher affinity to Insig-1 than Insig-2, is required for ubiquitination and degradation of Insig-1 in sterol-depleted cells. Sterols prevent Insig-1 ubiquitination and degradation by displacing gp78 from Insig-1, an event that results from sterol-induced binding of Scap to Insig-1. In addition to providing a mechanism for sterol-regulated degradation of Insig-1, these results help to explain why Scap is subject to endoplasmic reticulum retention upon Insig-1 binding, whereas 3-hydroxy-3-methylglutaryl coenzyme A reductase is ubiquitinated and degraded.
Lee
Joon No
JN
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Song
Baoliang
B
DeBose-Boyd
Russell A
RA
Ye
Jin
J
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D060285:Receptors, Autocrine Motility Factor; D018121:Receptors, Cytokine / Q000737:chemistry / Q000502:physiology*; D013261:Sterols / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*
C108626:INSIG1 protein, human; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018121:Receptors, Cytokine; C102196:SREBP cleavage-activating protein; D013261:Sterols; D025801:Ubiquitin; D006903:Hydroxymethylglutaryl CoA Reductases; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor; D044767:Ubiquitin-Protein Ligases