Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP

• DOI: 10.7554/elife.28766
• Publication Date: 2017-10-20T10:00:10Z
• Authors: Li Zhang; Prashant Rajbhandari; Christina Priest; Jaspreet Sandhu; Xiaohui Wu; Ryan Temel; Antonio Castrillo; Thomas Q de Aguia...; Tamer Sallam; Peter Tontonoz
• Keywords: Liver X receptor; Crosstalk

Cholesterol homeostasis is maintained through concerted action of the SREBPs and LXRs. Here, we report that RNF145, a previously uncharacterized ER membrane ubiquitin ligase, participates in crosstalk between these critical signaling pathways. RNF145 expression induced response to LXR activation high-cholesterol diet feeding. Transduction into mouse liver inhibits genes involved cholesterol biosynthesis reduces plasma levels. Conversely, acute suppression via shRNA-mediated knockdown, or chronic inactivation by genetic deletion, potentiates biosynthetic increases levels both plasma. Mechanistic studies show triggers ubiquitination SCAP on lysine residues within cytoplasmic loop essential for COPII binding, potentially inhibiting its transport Golgi subsequent processing SREBP-2. These findings define an additional mechanism linking hepatic sterol reciprocal actions SREBP-2