Sterol regulatory element-binding protein processing machinery (SREBP processing machinery) (SREBP processing machinery)

The Sterol Regulatory Element-Binding Protein (SREBP) processing machinery is a multi-protein system that governs cellular lipid homeostasis by regulating the activation of SREBP transcription factors. This machinery is composed of the sterol sensor SCAP (SREBP cleavage-activating protein), the ER-retention proteins Insig-1 and Insig-2, and two Golgi-resident enzymes, Site-1 Protease (S1P) and Site-2 Protease (S2P) (Brown & Goldstein, 1997, Cell). When cellular sterol levels are low, SCAP escorts SREBPs from the endoplasmic reticulum to the Golgi apparatus, where they are sequentially cleaved by S1P and S2P to release their active N-terminal transcription factor domains (Horton et al., 2002, J Clin Invest). These active fragments then translocate to the nucleus to upregulate genes involved in cholesterol and fatty acid biosynthesis. Dysregulation of this pathway is a key driver of metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), obesity, and type 2 diabetes, and it is also exploited by cancer cells to meet increased lipid demands for membrane synthesis (Kamisuki et al., 2009, Chem Biol). Pharmacological intervention targeting this machinery, such as SCAP inhibitors or S1P/S2P protease inhibitors, offers a therapeutic approach to treat dyslipidemia and metabolic syndrome (Hawkins et al., 2008, J Lipid Res).

Other names

SREBP activation pathwaySCAP/SREBP complexSREBP proteolytic processing systemSREBP-SCAP-Insig axis

Inhibition of SCAP-mediated transport of SREBP from the ER to the Golgi, or inhibition of proteolytic cleavage by Site-1 Protease (S1P) and Site-2 Protease (S2P) to prevent the release of active transcription factor domains.