Sterol regulatory element-binding protein maturation pathway (SREBP maturation pathway)

The Sterol Regulatory Element-Binding Protein (SREBP) maturation pathway is a fundamental regulatory mechanism that controls the synthesis and uptake of cholesterol and fatty acids in mammalian cells (Brown & Goldstein, 1997, Cell). SREBPs are synthesized as inactive precursors anchored in the endoplasmic reticulum (ER) membrane, where they form a complex with the SREBP cleavage-activating protein (SCAP), a sterol sensor. When cellular sterol levels decline, SCAP escorts SREBP to the Golgi apparatus, where it undergoes sequential proteolytic cleavage by Site-1 Protease (S1P) and Site-2 Protease (S2P) (Horton et al., 2002, J. Clin. Invest.). This process releases the amino-terminal bHLH-Zip domain, which translocates to the nucleus to activate the transcription of genes such as HMG-CoA reductase and fatty acid synthase. Dysregulation of this pathway is a hallmark of metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes, and it is increasingly recognized as a driver of lipid metabolism in cancer cells (Shimano & Sato, 2017, Nat. Rev. Endocrinol.). Pharmacological inhibition of the SREBP maturation pathway, through molecules like Fatostatin or S1P inhibitors, offers a therapeutic approach to lower lipid levels and improve insulin sensitivity (Kamisuki et al., 2009, J. Biol. Chem.).

Other names

SREBP processing pathwaySREBP activation pathwaySCAP-SREBP-S1P-S2P axisSREBP-1/2 maturation pathway

The pathway is targeted by inhibiting the transport of the SREBP-SCAP complex from the endoplasmic reticulum to the Golgi apparatus or by inhibiting the proteolytic activity of Site-1 Protease (S1P) and Site-2 Protease (S2P), thereby preventing the release and nuclear translocation of the active transcription factor domain (Brown & Goldstein, 1997; Kamisuki et al., 2009).