Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner
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...
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-08-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520352263 |
| _version_ | 1818957126712688640 |
|---|---|
| author | Wei Shao (邵威) Carolyn E. Machamer Peter J. Espenshade |
| author_facet | Wei Shao (邵威) Carolyn E. Machamer Peter J. Espenshade |
| author_sort | Wei Shao (邵威) |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T11:04:54Z |
| format | Article |
| id | doaj.art-e585a702e09745f580494db60e41e16b |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-20T11:04:54Z |
| publishDate | 2016-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-e585a702e09745f580494db60e41e16b2022-12-21T19:42:54ZengElsevierJournal of Lipid Research0022-22752016-08-0157815641573Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent mannerWei Shao (邵威)0Carolyn E. Machamer1Peter J. Espenshade2Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205To whom correspondence should be addressed; To whom correspondence should be addressed; Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205Sterol 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.http://www.sciencedirect.com/science/article/pii/S0022227520352263sterol regulatory element-binding protein cleavage activating proteinsterol regulatory element-binding proteinendoplasmic reticulum-to-Golgi transportendoplasmic reticulum |
| spellingShingle | Wei Shao (邵威) Carolyn E. Machamer Peter J. Espenshade Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner Journal of Lipid Research sterol regulatory element-binding protein cleavage activating protein sterol regulatory element-binding protein endoplasmic reticulum-to-Golgi transport endoplasmic reticulum |
| title | Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner |
| title_full | Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner |
| title_fullStr | Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner |
| title_full_unstemmed | Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner |
| title_short | Fatostatin blocks ER exit of SCAP but inhibits cell growth in a SCAP-independent manner |
| title_sort | fatostatin blocks er exit of scap but inhibits cell growth in a scap independent manner |
| topic | sterol regulatory element-binding protein cleavage activating protein sterol regulatory element-binding protein endoplasmic reticulum-to-Golgi transport endoplasmic reticulum |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520352263 |
| work_keys_str_mv | AT weishaoshàowēi fatostatinblockserexitofscapbutinhibitscellgrowthinascapindependentmanner AT carolynemachamer fatostatinblockserexitofscapbutinhibitscellgrowthinascapindependentmanner AT peterjespenshade fatostatinblockserexitofscapbutinhibitscellgrowthinascapindependentmanner |