【多选题】Regulation of HMG-CoA reductase synthesis by cholesterol is mediated by an elegant system of transcriptional regulation of the HMG-CoA gene. This gene, along with more than 20 other genes encoding enz...
A.
When newly synthesized, these proteins are embedded in the ER. Only the soluble regulatory domain fragment of an SREBP functions as a transcription activator. When cholesterol and oxysterol levels are high, SREBPs are held in the ER in a complex with another protein called SREBP cleavage-activating protein (SCAP), which in turn is anchored in the ER membrane by its interaction with a third membrane protein, Insig (insulin-induced gene protein).
B.
SCAP and Insig act as sterol sensors. When sterol levels are high, the Insig-SCAP-SREBP complex is retained in the ER membrane. When the level of sterols in the cell declines, the SCAP-SREBP complex is escorted by secretory proteins to the Golgi complex.
C.
There, two proteolytic cleavages of SREBP release a regulatory fragment, which enters the nucleus and activates transcription of its target genes, including those for HMG-CoA reductase, the LDL receptor protein, and other proteins needed for lipid synthesis.
D.
When sterol levels increase sufficiently, the proteolytic release of SREBP amino-terminal domains is again blocked, and proteasome degradation of the existing active domains results in rapid shutdown of the gene targets.