Ring finger protein 5 activates sterol regulatory element–binding protein 2 (SREBP2) to promote cholesterol biosynthesis via inducing polyubiquitination of SREBP chaperone SCAP
Journal
Journal of Biological Chemistry
Journal Volume
295
Journal Issue
12
Pages
3918
Date Issued
2020-03
Author(s)
Abstract
Sterol regulatory element-binding protein 2 (SREBP2) is the master transcription factor that regulates cholesterol metabolism. SREBP2 activation is regulated by SREBP chaperone SCAP. Here we show that ring finger protein 5 (RNF5), an endoplasmic reticulum-anchored E3 ubiquitin ligase, mediates the Lys-29-linked polyubiquitination of SCAP and thereby activates SREBP2. RNF5 knockdown inhibited SREBP2 activation and reduced cholesterol biosynthesis in human hepatoma cells, and RNF5 overexpression activated SREBP2. Mechanistic studies revealed that RNF5 binds to the transmembrane domain of SCAP and ubiquitinates the Lys-305 located in cytosolic loop 2 of SCAP. Moreover, the RNF5-mediated ubiquitination enhanced an interaction between SCAP luminal loop 1 and loop 7, a crucial event for SREBP2 activation. Notably, an overexpressed K305R SCAP variant failed to restore the SREBP2 pathway in SCAP-deficient cell lines. These findings define a new mechanism by which an ubiquitination-induced SCAP conformational change regulates cholesterol biosynthesis.
Subjects
E3 ubiquitin ligase; SREBP chaperone (SCAP); cholesterol; endoplasmic reticulum (ER); lipid metabolism; polyubiquitin chain; post-translational modification (PTM); ring finger protein 5 (RNF5); sterol regulatory element-binding protein (SREBP)
SDGs
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Type
journal article