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http://hdl.handle.net/10553/35318
Title: | Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP | Authors: | Zhang, Li Rajbhandari, Prashant Priest, Christina Sandhu, Jaspreet Wu, Xiaohui Temel, Ryan Castrillo Viguera, Antonio De Aguiar Vallim, Thomas Q. Sallam, Tamer Tontonoz, Peter |
UNESCO Clasification: | 320502 Endocrinología 2407 Biología celular 3206 Ciencias de la nutrición |
Keywords: | Liver-X-Receptor Cleavage-Activating protein HMG coa reductase LXR-Alpha Deficient mice, et al |
Issue Date: | 2017 | Journal: | eLife | Abstract: | Cholesterol homeostasis is maintained through concerted action of the\r\nSREBPs and LXRs. Here, we report that RNF145, a previously\r\nuncharacterized ER membrane ubiquitin ligase, participates in crosstalk\r\nbetween these critical signaling pathways. RNF145 expression is induced\r\nin response to LXR activation and high-cholesterol diet feeding.\r\nTransduction of RNF145 into mouse liver inhibits the expression of genes\r\ninvolved in cholesterol biosynthesis and reduces plasma cholesterol\r\nlevels. Conversely, acute suppression of RNF145 via shRNA-mediated\r\nknockdown, or chronic inactivation of RNF145 by genetic deletion,\r\npotentiates the expression of cholesterol biosynthetic genes and\r\nincreases cholesterol levels both in liver and plasma. Mechanistic\r\nstudies show that RNF145 triggers ubiquitination of SCAP on lysine\r\nresidues within a cytoplasmic loop essential for COPII binding,\r\npotentially inhibiting its transport to Golgi and subsequent processing\r\nof SREBP-2. These findings define an additional mechanism linking\r\nhepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR\r\npathways. | URI: | http://hdl.handle.net/10553/35318 | ISSN: | 2050-084X | DOI: | 10.7554/eLife.28766.001 | Source: | eLife [ISSN 2050-084X], v. 6, e28766, (Octubre 2017) |
Appears in Collections: | Artículos |
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