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J Lipid Res. 2016 Aug;57(8):1564-73. doi: 10.1194/jlr.M069583. Epub 2016 Jun 20.

Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner.

Author information

1
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
2
Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205 peter.espenshade@jhmi.edu.

Abstract

Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of cellular lipid homeostasis and activate expression of genes required for fatty acid, triglyceride, and cholesterol synthesis and uptake. SREBP cleavage activating protein (SCAP) plays an essential role in SREBP activation by mediating endoplasmic reticulum (ER)-to-Golgi transport of SREBP. In the Golgi, membrane-bound SREBPs are cleaved sequentially by the site-1 and site-2 proteases. Recent studies have shown a requirement for the SREBP pathway in the development of fatty liver disease and tumor growth, making SCAP a target for drug development. Fatostatin is a chemical inhibitor of the SREBP pathway that directly binds SCAP and blocks its ER-to-Golgi transport. In this study, we determined that fatostatin blocks ER exit of SCAP and showed that inhibition is independent of insulin-induced gene proteins, which function to retain the SCAP-SREBP complex in the ER. Fatostatin potently inhibited cell growth, but unexpectedly exogenous lipids failed to rescue proliferation of fatostatin-treated cells. Furthermore, fatostatin inhibited growth of cells lacking SCAP Using a vesicular stomatitis virus glycoprotein (VSVG) trafficking assay, we demonstrated that fatostatin delays ER-to-Golgi transport of VSVG. In summary, fatostatin inhibited SREBP activation, but fatostatin additionally inhibited cell proliferation through both lipid-independent and SCAP-independent mechanisms, possibly by general inhibition of ER-to-Golgi transport.

KEYWORDS:

endoplasmic reticulum; endoplasmic reticulum-to-Golgi transport; sterol regulatory element-binding protein; sterol regulatory element-binding protein cleavage activating protein

PMID:
27324795
PMCID:
PMC4959871
DOI:
10.1194/jlr.M069583
[Indexed for MEDLINE]
Free PMC Article

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