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Updated: Sep 2, 2025
09:44
High-throughput Screening for Chemical Modulators of Post-transcriptionally Regulated Genes
Published on: March 3, 2015
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Post-Translational Regulation of HMG CoA Reductase.
Youngah Jo1, Russell A DeBose-Boyd1
1Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas 75390-9046, USA.
Cold Spring Harbor Perspectives in Biology
|August 8, 2022
Summary
Feedback control of cholesterol synthesis enzyme HMGCR involves ubiquitination and ER-associated degradation (ERAD). Geranylgeranyl pyrophosphate (GGpp) and UBIAD1 modulate this process, balancing sterol and nonsterol isoprenoid production in vivo.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Regulation
Background:
- 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is a key enzyme in cholesterol and isoprenoid synthesis.
- HMGCR activity is tightly regulated by feedback mechanisms to maintain cellular homeostasis.
- Essential nonsterol isoprenoids must be produced, while cholesterol accumulation is prevented.
Purpose of the Study:
- To elucidate the feedback control mechanism of HMGCR.
- To investigate the role of ubiquitination and ER-associated degradation (ERAD) in HMGCR regulation.
- To understand how geranylgeranyl pyrophosphate (GGpp) and UBIAD1 influence HMGCR ERAD and metabolic balance.
Main Methods:
- Focus on sterol-induced ubiquitination and ER-associated degradation (ERAD) of HMGCR.
- Analysis of GGpp's augmentation of HMGCR ERAD.
- Investigation of GGpp-regulated intracellular trafficking of UBIAD1 and its effect on HMGCR ERAD.
- Characterization of mouse models to study in vivo regulation.
Main Results:
- Sterol-induced ubiquitination targets HMGCR for ERAD.
- GGpp enhances HMGCR ERAD.
- GGpp-regulated UBIAD1 trafficking inhibits HMGCR ERAD, balancing sterol and nonsterol isoprenoid synthesis.
- Mouse models confirm the role of sterol-accelerated, UBIAD1-modulated ERAD in cholesterol metabolism.
Conclusions:
- HMGCR degradation via ERAD is a critical feedback mechanism.
- UBIAD1 plays a key role in modulating HMGCR ERAD and balancing isoprenoid synthesis.
- Sterol-accelerated, UBIAD1-modulated ERAD is crucial for in vivo regulation of HMGCR and cholesterol metabolism.
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