The SREBP Pathway: Stadtman's Paradigm Applied to Cholesterol

Cholesterol is an essential component of animal cell membranes, and its concentration is tightly controlled by a feedback system that operates primarily at the transcriptional level. This system consists of a membrane‐bound transcription factor, SREBP‐2, and a polytopic membrane protein, Scap, that binds cholesterol and monitors its concentration in membranes of the endoplasmic reticulum (ER). When sterol levels are low, Scap transports membrane‐bound SREBP from ER to Golgi. In the Golgi, SREBP is processed sequentially by two membrane‐bound proteases that release the N‐terminal half of SREBP, allowing it to enter the nucleus where it activates genes encoding proteins that mediate cholesterol synthesis and uptake. When excess cholesterol builds up in ER membranes, Scap binds cholesterol and undergoes a conformation change that elicits binding to Insig, an ER anchor protein. Insig prevents transport of the Scap/SREBP complex to the Golgi, thus terminating cholesterol synthesis and uptake. Feedback regulation of SREBP processing is triggered by delivery of exogenous LDL‐derived cholesterol to ER membranes. This delivery results from receptor‐mediated endocytosis of LDL, followed by hydrolysis of the cholesteryl esters of LDL in lysosomes and transport of the released cholesterol across lysosomal membranes. Cholesterol is exported from lysosomes by a hydrophobic handoff from a soluble lysosomal protein, NPC2, to a membrane‐bound lysosomal protein, NPC1. This handoff protects cholesterol from the aqueous environment and prevents the toxic crystallization of cholesterol. Through these coordinated mechanisms, animal cells can regulate their membrane cholesterol content with precise limits.