Inhibition of cholesterol biosynthesis through RNF145-dependent ubiquitination of SCAP
Li Zhang,
Prashant Rajbhandari,
Christina Priest,
Jaspreet Sandhu,
Xiaohui Wu,
Ryan Temel,
Antonio Castrillo,
Thomas Q de Aguiar Vallim,
Tamer Sallam,
Peter Tontonoz
Affiliations
Li Zhang
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
Prashant Rajbhandari
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
Christina Priest
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
Jaspreet Sandhu
Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States
Xiaohui Wu
Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, United States
Ryan Temel
Saha Cardiovascular Research Center, University of Kentucky, Lexington, United States; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, United States
Antonio Castrillo
Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-Universidad Autónoma de Madrid, Unidad de Biomedicina-Universidad de Las Palmas de Gran Canaria (Unidad asociada al CSIC), Las Palmas de Gran Canaria, Spain; Instituto Universitario de Investigaciones Biomédicas y Sanitarias, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain
Thomas Q de Aguiar Vallim
Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, United States
Tamer Sallam
Department of Medicine, Division of Cardiology, University of California, Los Angeles, Los Angeles, United States
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 is induced in response to LXR activation and high-cholesterol diet feeding. Transduction of RNF145 into mouse liver inhibits the expression of genes involved in cholesterol biosynthesis and reduces plasma cholesterol levels. Conversely, acute suppression of RNF145 via shRNA-mediated knockdown, or chronic inactivation of RNF145 by genetic deletion, potentiates the expression of cholesterol biosynthetic genes and increases cholesterol levels both in liver and plasma. Mechanistic studies show that RNF145 triggers ubiquitination of SCAP on lysine residues within a cytoplasmic loop essential for COPII binding, potentially inhibiting its transport to Golgi and subsequent processing of SREBP-2. These findings define an additional mechanism linking hepatic sterol levels to the reciprocal actions of the SREBP-2 and LXR pathways.
