Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake.
This paper describes a convergent mechanism for the feedback control of cholesterol synthesis and uptake mediated by SREBPs, membrane bound transcription factors. Endoplasmic reticulum (ER) bound SREBPs form complexes with Scap, a polytopic ER protein. In sterol-overloaded cells, Scap/SREBP binds to Insig-1, which retains the complex in the ER. Upon sterol deprivation, the Scap/SREBP complex dissociates from Insig-1, which is then ubiquitinated on lysines 156 and 158 and degraded in proteasomes. Scap/SREBP moves to the Golgi, where SREBP is processed to liberate a nuclear fragment that activates genes for cholesterol synthesis and uptake and the gene for Insig-1. Ubiquitination is not necessary for release of Scap/SREBP from Insig-1, but it establishes a requirement for synthesis of new Insig-1 for feedback inhibition. When the new Insig-1 and cholesterol converge on Scap, Scap/SREBP binds to Insig-1, preventing ubiquitination. The Insig-1/Scap/SREBP complex accumulates in the ER, ready for liberation when the cell is again sterol deprived.
Gong
Yi
Y
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Lee
Joon No
JN
Lee
Peter C W
PC
Goldstein
Joseph L
JL
Brown
Michael S
MS
Ye
Jin
J
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D025461:Feedback, Physiological / Q000502:physiology*; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051779:Sterol Regulatory Element Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
D006888:Hydroxycholesterols; C108626:INSIG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051779:Sterol Regulatory Element Binding Proteins; D013261:Sterols; D025801:Ubiquitin; C007997:25-hydroxycholesterol; D002784:Cholesterol; D008239:Lysine