Identification of a degradation signal at the carboxy terminus of SREBP2: A new role for this domain in cholesterol homeostasis

Significance Sterol regulatory element-binding proteins (SREBPs) are transcription factors that control production of cholesterol and other lipids. In endoplasmic reticulum (ER) membranes, SREBPs form complexes with Scap, a cholesterol-sensing membrane protein. When cholesterol levels are low, Scap escorts SREBPs from the ER to the Golgi where proteolytic cleavage releases the transcription factor domain that turns on genes involved in cholesterol synthesis. The remainder of SREBP still bound to Scap must be eliminated so that Scap can be recycled to bind additional SREBPs. Here, we discover a degradation signal in SREBP that mediates clearance of the cleaved SREBP fragments from Scap. Such clearance is essential for the recycling of Scap and thus it is a central step in regulation of cholesterol homeostasis.