ArticleThe Journal of biological chemistry2014
Sequential actions of the AAA-ATPase valosin-containing protein (VCP)/p97 and the proteasome 19 S regulatory particle in sterol-accelerated, endoplasmic reticulum (ER)-associated degradation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 54 citations in OpenAlex.
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- Allosteric regulation of UBIAD1 trafficking from ER to Golgi revealed by chemical genetic screening.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The Role of Cholesterol Metabolism and Its Regulation in Tumor Development.Cancer medicine · 2025Review
- Genetic evidence for the liver-brain axis: lipid metabolism and neurodegenerative disease risk.Lipids in health and disease · 2025Article
- Direct binding to sterols accelerates endoplasmic reticulum-associated degradation of HMG CoA reductase.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Mechanisms of 3-Hydroxyl 3-Methylglutaryl CoA Reductase in Alzheimer's Disease.International journal of molecular sciences · 2023Review
- Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases.Molecular neurodegeneration · 2023Review
- Inhibition of the Proteasome Regulator PA28 Aggravates Oxidized Protein Overload in the Diabetic Rat Brain.Cellular and molecular neurobiology · 2023Article
- Post-Translational Regulation of HMG CoA Reductase.Cold Spring Harbor perspectives in biology · 2022Review
- Regulated degradation of HMG CoA reductase requires conformational changes in sterol-sensing domain.Nature communications · 2022Article
- Article
- Sterol auto-oxidation adversely affects human motor neuron viability and is a neuropathological feature of amyotrophic lateral sclerosis.Scientific reports · 2021Article
- Post-translational control of the long and winding road to cholesterol.The Journal of biological chemistry · 2020Review
- Neutral Lipid Cacostasis Contributes to Disease Pathogenesis in Amyotrophic Lateral Sclerosis.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2020Article
- Schnyder corneal dystrophy-associated UBIAD1 is defective in MK-4 synthesis and resists autophagy-mediated degradation.Journal of lipid research · 2020Article
- Mechanisms and regulation of cholesterol homeostasis.Nature reviews. Molecular cell biology · 2020Review
- Enhanced ER-associated degradation of HMG CoA reductase causes embryonic lethality associated witheLife · 2020Article
- Direct visualization of degradation microcompartments at the ER membrane.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Cytochrome P450 endoplasmic reticulum-associated degradation (ERAD): therapeutic and pathophysiological implications.Acta pharmaceutica Sinica. B · 2020Review
- Degradation of integral membrane proteins modified with the photosensitive degron module requires the cytosolic endoplasmic reticulum-associated degradation pathway.Molecular biology of the cell · 2019Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
Accelerated endoplasmic reticulum (ER)-associated degradation (ERAD) of the cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase results from its sterol-induced binding to ER membrane proteins called Insig-1 and Insig-2. This binding allows for subsequent ubiquitination of reductase by Insig-associated ubiquitin ligases. Once ubiquitinated, reductase becomes dislocated from ER membranes into the cytosol for degradation by 26 S proteasomes through poorly defined reactions mediated by the AAA-ATPase valosin-containing protein (VCP)/p97 and augmented by the nonsterol isoprenoid geranylgeraniol. Here, we report that the oxysterol 25-hydroxycholesterol and geranylgeraniol combine to trigger extraction of reductase across ER membranes prior to its cytosolic release. This conclusion was drawn from studies utilizing a novel assay that measures membrane extraction of reductase by determining susceptibility of a lumenal epitope in the enzyme to in vitro protease digestion. Susceptibility of the lumenal epitope to protease digestion and thus membrane extraction of reductase were tightly regulated by 25-hydroxycholesterol and geranylgeraniol. The reaction was inhibited by RNA interference-mediated knockdown of either Insigs or VCP/p97. In contrast, reductase continued to become membrane-extracted, but not cytosolically dislocated, in cells deficient for AAA-ATPases of the proteasome 19 S regulatory particle. These findings establish sequential roles for VCP/p97 and the 19 S regulatory particle in the sterol-accelerated ERAD of reductase that may be applicable to the ERAD of other substrates.
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