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Analysis of SCAP N-glycosylation and Trafficking in Human Cells
Published on: November 8, 2016
The compound LY295427 antagonizes 25-hydroxycholesterol through binding to INSIG
Xing-Yan Wen1, De-Jie Zhang2, Li-Ming He2
1State Key Laboratory of Metabolism and Regulation in Complex Organisms, College of Life Sciences, Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan, China.
Abstract:
25-Hydroxycholesterol (25-HC) regulates cholesterol metabolism by inhibiting the maturation of SREBP and promoting the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). The compound LY295427 can reverse 25-HC-mediated suppression of SREBP processing, but the mechanism is unclear. In addition, it is unknown whether LY295427 is able to antagonize the sterol-regulated degradation of HMGCR. In this study, we found that LY295427 prevented the 25-HC-induced interaction between SREBP cleavage-activating protein and INSIG-1 and caused the translocation of SREBP cleavage-activating protein to the Golgi even in the presence of 25-HC. Using a photoreactive LY295427 probe, we demonstrated that it directly bound to INSIG-1, which could be competed off by 25-HC. In addition, LY295427 blocked 25-HC-induced ubiquitination and degradation of HMGCR. Together, this study suggests that LY295427 competes with 25-HC to bind INSIG and therefore blunts 25-HC-induced inhibition of SREBP processing and degradation of HMGCR.
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