Question

Discuss how cells control the level of cholesterol via regulated intra-membrane proteolysis of signaling protein/s.

Answer 1

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that activate genes involved in cholesterol synthesis.  SREBP-2 is responsible for cholesterol-related genes, such as HMG-CoA reductase, and the LDL receptor, which imports circulating LDL cholesterol. SREBP-1a targets both sets of genes.

Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors are critical regulators of genes involved in cholesterol/lipid homeostasis. After site-1 protease cleavage of the inactive SREBP transmembrane precursor protein, Regulated intramembrane proteolysis RIP of the anchor intermediate by site-2 protease generates the mature transcription factor.

The negative-feedback loop, switching on the transcription of target genes upon low cholesterol levels, is achieved via binding of transcriptional activators to the sterol regulatory element. This element is present in promoter regions near encoding genes. RIP also helps control lipid levels inside cells. When a transmembrane protein of the endoplasmic reticulum called SCAP (sterol regulatory- element-binding protein (SREBP) cleavage-activating protein) detects a fall in available levels of sterols, it transports SREBP from the endoplasmic reticulum to the Golgi body.