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Gene Transcription, Proteolysis and Membrane Lipids

Gene Transcription, Proteolysis and Membrane Lipids

An interesting example of transcriptional control occurs to maintain the balance of lipids in biological membranes. The phospholipids and sphingolipids in membranes are extremely heterogeneous, owing to the diversity of head groups and acyl chain composition. Given this great diversity, it is remarkable the different cells are able to maintain the specificity of lipid types in different cells, in different membranes within cells, and within a given leaflet of a membrane (remember our discussion of lipid rafts). How can the cell regulate the type of lipids that it synthesizes? What controls the transcription of genes for lipid synthesis?

Regulation of transcription of these genes appears to be controlled by multidomain proteins that bind to sterol response elements in the DNA. The proteins, called Sterol Response Element Binding Proteins (SREBPs) are activated by proteolysis to release a transcription factor domain which migrates to the nucleus. Proteolysis of SREBP occurs in the Golgi by resident proteases. The SREBP in the Golgi is in complex with another protein, SREP cleavage-activating protein (SCAP), which facilitates movement of the SREBP to the Golgi from its site of synthesis in the endoplasmic reticulum. Lipid regulation occurs when fatty acids, cholesterol, or PL derivatives like phosphoethanolamine (from ceramide) inhibits proteolytic activation of the SREBP. Regulation depends on whether or not SCAP "ferries" SREBP to the Golgi. It appears that SCAP binds to SREP and transfers it to the Golgi membrane, but only when sterol levels are low. When cholesterol is high, it binds to the transmembrane domain of SCAP and prevents SCAP from interacting with SREP and transferring it to the Golgi.

Auxin, a major plant hormone that induces gene expression, also seems to activate transcription through proteolysis. When bound to its soluble cytoplasmic receptors, ubiquitin protein ligase SCFTIR1, it activates proteolysis of protein that inhibits transcription.