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The Central Role of Insig Proteins in Regulating Cholesterol Homeostasis
Author(s) -
Goldstein Joseph L
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a146-f
Subject(s) - sterol regulatory element binding protein , endoplasmic reticulum , golgi apparatus , microbiology and biotechnology , transcription factor , biochemistry , chemistry , proteolysis , biology , gene , enzyme
The SREBP pathway is the process by which Sterol Regulatory Element‐binding Proteins (SREBPs) are transported from the endoplasmic reticulum (ER) to the Golgi apparatus where they undergo regulated intramembrane proteolysis to release a cytosolic fragment that enters the nucleus and activates transcription of ~30 genes required for synthesis of cholesterol and other lipids. The process is under feedback control by the end‐product cholesterol, which binds to Scap, a polytopic membrane protein that escorts SREBPs from ER to Golgi. Cholesterol binding to Scap causes a conformational change in the protein that triggers its binding to Insig‐1 or Insig‐2, a pair of ER anchor proteins that trap the Scap/SREBP complex in the ER, thereby blocking proteolysis of SREBPs and down‐regulating lipid synthesis. Insig proteins also mediate the sterol‐triggered proteosomal degradation of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, a rate‐limiting enzyme in cholesterol synthesis. In liver, transcription of the two Insig genes are regulated reciprocally by insulin and SREBPs in a process that assures the constant availability of one or the other Insig proteins. Insigs are central to the regulation of membrane lipid synthesis (for review, see J.L. Goldstein, R.A. DeBose‐Boyd, and M.S. Brown, Cell , 124 : –46, 2006). The elaborate mechanisms of control of Insigs will be discussed.