The SREBP Pathway: Gene Regulation through Sterol Sensing and Gated Protein Trafficking

Cholesterol is an essential component of mammalian cell membranes. Sufficient levels of cellular cholesterol are required for the integrity and impermeability of the plasma membrane, for the proper assembly of cell surface lipid rafts and caveolae, and for the posttranslational modification of at least one protein, the morphogen Hedgehog. Regulation of cholesterol levels in the body is highly essential. In this regard, this chapter outlines the molecular mechanism that mammalian cells utilize to maintain proper cholesterol homeostasis. Sterol regulatory element-binding proteins (SREBPs) transmit information to the nucleus about the sterol content of membranes. To date, in mammalian cells SREBPs have been shown to directly activate more than thirty genes involved in the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids. The SREBP pathway has also been identified and studied in cells of non-vertebrates including yeast, worms, and insects. This chapter focuses on mammals. It describes the mechanism for sterol mediated regulation of the processing of SREBP. Finally, the study states that the molecular switch that controls sterol metabolism in animal cells is a simple hexapeptide targeting signal (MELADL) in a single membrane protein (Scap). Future research areas need to be targeted at exploring the question of how the Scap and Insig discriminate between cholesterol and oxysterol and what is the nature of the conformational change upon sterol binding that allows complex formation. The answers to these questions await detailed molecular structures of Scap, Insig, and the Scap–Insig complex.