Cholesterol homeostasis: another twist on eSCAPe from the ER

Abstract

It is essential for mammalian cells to tightly regulate cholesterol content in their membranes. To this aim, they use a variety of feedback mechanisms that control cholesterol biosynthesis, storage as esters, and import from and export to circulating lipoproteins. The control of cellular cholesterol synthesis involves a fascinating series of regulated membrane-trafficking events. Recently, more details of the underlying mechanism have emerged.Key to cholesterol regulation is a family of membrane-bound transcription factors – sterol response element binding proteins (SREBPs) – which control enzyme levels in cholesterol synthesis, such as HMG-CoA reductase, as well as the synthesis of low-density lipoprotein (LDL)-receptors, which mediates endocytosis of cholesterol-rich LDL particles.Newly synthesized SREBPs form a complex in the endoplasmic reticulum (ER) with the polytopic membrane protein SREBP-cleavage activating protein (SCAP). To be activated, SREBPs must exit the ER complexed with their escort protein SCAP, and move to the Golgi. Here, SREBP is cleaved by two Golgi-localized proteases, S1P and S2P. This cleavage event releases the soluble NH2-terminal domain of SREBP, which then can enter the nucleus as an active, positive transcription factor. Thus, SCAP plays a crucial role in the regulation of ER export of SREBPs via COP II coated vesicles.SCAP contains a sterol-sensing domain, a segment that includes five of its eight transmembrane helices. In situations of lowered cellular cholesterol, or when point mutations are introduced into the sterol sensing domain of SCAP, SCAP can exit the ER and escort SREBP to the Golgi complex. Now, Brown et al. demonstrate in vitro that cholesterol causes a conformational change in SCAP, as detected by the unmasking of closely spaced trypsin cleavage sites [1xCholesterol addition to ER membranes alters conformation of SCAP, the SREBP escort protein that regulates cholesterol metabolism. Brown, A. et al. Mol. Cell. 2002; 10: 237–245Abstract | Full Text | Full Text PDF | PubMed | Scopus (232)See all References[1]. In addition, Yang et al. show that high cholesterol causes SCAP to bind to a novel ER membrane protein, INSIG-1, and that this strongly correlates with the inhibition of ER exit of SCAP, and SREBPs [2xCrucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Yang, T. et al. Cell. 2002; 110: 489–500Abstract | Full Text | Full Text PDF | PubMed | Scopus (515)See all References[2].In sterol-depleted cells SCAP does not bind INSIG-1, thus enabling the SREBP/SCAP complex to leave the ER for the Golgi. Mutant SCAP that is unable to bind sterols also does not bind INSIG-1. Earlier studies from the Goldstein and Brown laboratory identified INSIG-1 as an mRNA with increased abundance in livers of transgenic mice that overexpress SREBP-1a. The new data show that INSIG-1 acts in the regulated ER retention of SCAP.Finally, Espenshade et al. demonstrate that sterols block incorporation of SCAP into classic COP II-coated vesicles [3xSterols block binding of COP II proteins to SCAP, thereby controlling SCAP sorting in ER. Espenshade, P. et al. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11694–11699Crossref | Scopus (85)See all References[3]. Furthermore, sterols block the Sar1p by dependent binding of the COP II proteins Sec23/34p to SCAP in vitro. These studies deepen our understanding of how ER exit of SCAP is controlled. As time goes by, we can be sure to expect more surprising insights into this sophisticated cellular feedback mechanism.