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The cellular function of SCAP in metabolic signaling

Lee, Sun Hee, Lee, Jae-Ho, Im, Seung-Soon·2020·Experimental & Molecular Medicine
DOI 10.1038/s12276-020-0430-0PMC PMC7272406
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Abstract

Sterol regulatory element binding protein (SREBP) cleavage activating protein (SCAP) is a key regulator of SREBP maturation. SCAP induces translocation of SREBP from the endoplasmic reticulum to the Golgi apparatus, allowing it to regulate cellular triglyceride and cholesterol levels. Previous studies have shown that suppression of SREBP activation in SCAP conditional knockout mice reduced the accumulation of intracellular triglycerides, which eventually causes the development of metabolic diseases such as atherosclerosis, diabetes, hepatic steatosis, and insulin resistance. However, despite the significance of SCAP as a regulator of SREBP, its function has not been thoroughly discussed. In this review, we have summarized the function of SCAP and its regulatory proteins. Furthermore, we discuss recent studies regarding SCAP as a possible therapeutic target for hypertriglyceridemia and hyperlipidemia.

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Fig. 1 Schematic model of the domain organization and processing mechanism of SCAP. a SCAP proteins consist of an amino-terminal domain of eight transmembrane helices and a carboxyl-terminal WD40 domain. Transmembrane helices 2-6 of SCAP constitute a sterol-sensing domain. b When mammalian cells are deprived of cholesterol, SCAP escorts SREBPs in COPII vesicles from the ER to the Golgi. Two Golgi proteases (S1P and S2P) then sequentially cleave SREBPs. The NH2-terminal region of SREBPs moves to the nucleus and activates the transcription of target genes. To date, SREBPs are known to directly enhance the transcription of more than 30 genes needed for the uptake and synthesis of cholesterol, fatty acids, triglycerides, and phospholipids. Despite acting in diverse biosynthetic pathways, the activity of each SREBP isoform is regulated by sterols and SCAP. COPII, coat protein II; ER, endoplasmic reticulum; INSIG, insulin-induced gene; S1P, site-1 protease; S2P, site-2 protease; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBP, Sterol regulatory element-binding protein.
Fig. 1 Schematic model of the domain organization and processing mechanism of SCAP. a SCAP proteins consist of an amino-terminal domain of eight transmembrane helices and a carboxyl-terminal WD40 domain. Transmembrane helices 2-6 of SCAP constitute a sterol-sensing domain. b When mammalian cells are deprived of cholesterol, SCAP escorts SREBPs in COPII vesicles from the ER to the Golgi. Two Golgi proteases (S1P and S2P) then sequentially cleave SREBPs. The NH2-terminal region of SREBPs moves to the nucleus and activates the transcription of target genes. To date, SREBPs are known to directly enhance the transcription of more than 30 genes needed for the uptake and synthesis of cholesterol, fatty acids, triglycerides, and phospholipids. Despite acting in diverse biosynthetic pathways, the activity of each SREBP isoform is regulated by sterols and SCAP. COPII, coat protein II; ER, endoplasmic reticulum; INSIG, insulin-induced gene; S1P, site-1 protease; S2P, site-2 protease; SCAP, SREBP cleavage-activating protein; SRE, sterol regulatory element; SREBP, Sterol regulatory element-binding protein.CC BY · PubMed Central
Fig. 2 The function of SREBP-SCAP in lipid metabolism. Activation of SCAP–SREBP as the master regulator of lipid metabolism stimulates the transcription of enzymes required for de novo lipogenesis and receptors that mediate the uptake of fatty acids released by lipolysis.
Fig. 2 The function of SREBP-SCAP in lipid metabolism. Activation of SCAP–SREBP as the master regulator of lipid metabolism stimulates the transcription of enzymes required for de novo lipogenesis and receptors that mediate the uptake of fatty acids released by lipolysis.CC BY · PubMed Central
Fig. 3 Small-molecule inhibitors of the SCAP-SREBP complex. a Fatostatin is a chemical inhibitor of the SREBP pathway that directly binds SCAP and blocks its ER-to-Golgi transport. b Betulin enhances the binding of SCAP with INSIGs, thereby promoting the retention of SREBPs in the ER. c Xanthohumol, a prenylated flavonoid in hops, is an antagonist of SREBP.
Fig. 3 Small-molecule inhibitors of the SCAP-SREBP complex. a Fatostatin is a chemical inhibitor of the SREBP pathway that directly binds SCAP and blocks its ER-to-Golgi transport. b Betulin enhances the binding of SCAP with INSIGs, thereby promoting the retention of SREBPs in the ER. c Xanthohumol, a prenylated flavonoid in hops, is an antagonist of SREBP.CC BY · PubMed Central

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Citations

Cites

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Metadata

Authors
Lee, S. H., Lee, J.-H., & Im, S.-S.
ORCID
Im, Seung-Soon
Venue
Experimental & Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2020-05
Volume
52
Issue
5
Pages
724-729
ISSN
  • 1226-3613
  • 2092-6413
DOI
10.1038/s12276-020-0430-0
PMC
PMC7272406
Cited by
96
References
4
Language
en
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