Rto Golgi Transport and Proteolytic Activation Control the Activity of Srebp Transcription Factors

Cholesterol-dependent transcriptional regulation often depends on 10-base-pair sterol regulatory elements (SREs), or SRE half-sites, in the promoters of regulated target genes. As you might expect from the discussion of transcriptional control in Chapter 11, the interaction of cholesterol-dependent SRE-binding proteins (SREBPs) with these response elements modulates the expression of the target genes. What you

▲ FIGURE 18-17 Model for cholesterol-sensitive control of SREBP activation mediated by insig-1(2) and SCAP. The cellular pool of cholesterol is monitored by combined action of insig-1(2) and SCAR both transmembrane proteins located in the ER membrane. (a) When cholesterol levels are high, insig-1(2) binds to the sterol-sensing domain in SCAR anchoring the SCAR/SREBR complex in the ER membrane. (b) The dissociation of insig-1(2) from SCAR at low cholesterol levels allows the might not expect is that the SREBP-mediated pathway, whereby cholesterol controls the expression of proteins engaged in cholesterol metabolism, begins in the ER and includes at least two other proteins besides SREBP.

When cells have adequate concentrations of cholesterol, SREBP is found in the ER membrane complexed with SCAP (SREBP cleavage-activating protein), insig-1 (or its close homolog insig-2), and perhaps other proteins (Figure 18-17, left). SREBP has three distinct domains: an N-terminal cy-tosolic domain that includes a basic helix-loop-helix (bHLH) DNA-binding motif (see Figure 11-22b) and functions as a transcription factor, a central membrane-anchoring domain containing two transmembrane a helices, and a C-terminal cytosolic regulatory domain. SCAP has eight transmembrane a helices and a large C-terminal cytosolic domain that interacts with the regulatory domain of SREBP. Five of the transmembrane helices in SCAP form a sterol-sensing domain, similar to that in HMG-CoA reductase. The sterol-sensing domain in SCAP binds tightly to insig-1(2), but only at high cellular cholesterol levels. When insig-1(2) is tightly bound to SCAP, it blocks the binding of SCAP to COP II vesicle coat proteins and thus prevents incorporation of the SCAP/SREBP complex into ER-to-Golgi transport vesicles (see Chapter 17).

SCAR/SREBR complex to move to the Golgi complex by vesicular transport. (Right) The sequential cleavage of SREBR by the site 1 and site 2 proteases (SIR S2R) associated with the Golgi membrane releases the N-terminal bHLH domain, called nuclear SREBR (nSREBR). After translocating into the nucleus, nSREBR controls the transcription of genes containing sterol regulatory elements (SREs) in their promoters. [Adapted from T F Osborne, 2001, Genes Devel. 15:1873; see T. Yang et al., 2002, Cell 110:489.]

When cellular cholesterol levels drop, insig-1(2) no longer binds to SCAP, and the SCAP/SREBP complex can move from the ER to the Golgi apparatus (Figure 18-17, right). In the Golgi, SREBP is cleaved sequentially at two sites by two membrane-bound proteases, S1P and S2P. The second intramembrane cleavage at site 2 releases the N-terminal bHLH-containing domain into the cytosol. This fragment, called nSREBP (nuclear SREBP), binds directly to the nuclear import receptor and is rapidly translocated into the nucleus (see Figure 12-21). In the nucleus, nSREBP activates the transcription of genes containing SREs in their promoters, such as those encoding the LDL receptor and HMG-CoA reductase. After cleavage of SREBP in the Golgi, SCAP apparently recycles back to the ER where it can interact with insig-1(2) and another SREBP molecule. High-level transcription of SRE-controlled genes requires the ongoing generation of new nSREBP because it is degraded fairly rapidly by the ubiquitin-mediated proteasomal pathway (Chapter 3). The rapid generation and degradation of nSREBP help cells respond quickly to changes in levels of intracellular cholesterol.

In the insig-1(2)/SCAP/SREBP pathway for controlling cellular cholesterol metabolism, the cell exploits intercom-partmental movements (ER ^ Golgi ^ cytosol ^ nucleus), regulated by sterol-dependent protein-protein interactions, and post-translational proteolytic cleavage to activate a membrane-bound transcription factor. Cleavage of SREBP in this pathway is one of several known examples of regulated intramembraneproteolysis (RIP). For instance, RIP activates transcription factors in the Notch signaling pathway (Chapter 14) and in the unfolded-protein response (Chapter 16). RIP is also responsible for the generation of the toxic amyloid P peptides that contribute to the onset of Alzheimer's disease (see Figure 14-30).

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