ArticleProceedings of the National Academy of Sciences of the United States of America2020
A key mammalian cholesterol synthesis enzyme, squalene monooxygenase, is allosterically stabilized by its substrate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 84 citations in OpenAlex.
- Squalene Epoxidase: Its Regulations and Links with Cancers.International journal of molecular sciences · 2024Pooled it
- Deciphering the Mechanisms of Statin-Ezetimibe Drug Combinations Using Boolean Logical Modeling and Transcriptomic Data.CPT: pharmacometrics & systems pharmacology · 2026Article
- Low temperature rather than hypoxia drives cholesterol synthesis and oxygen consumption in plateau zokors.iScience · 2026Article
- Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
- Research Progress on Anticancer Mechanism of Ginsenoside Regulating Tumor Microenvironment.Current issues in molecular biology · 2026Review
- Designer Solid Self-Emulsifying Nanovaccines Enable Dual Modulation of Dendritic Cells and T Cells for Potent Antitumor Immunity.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.Nature communications · 2025Article
- Genes involved in the regulation of alkaloid and flavonoid biosynthesis in different tissues of Sophora tonkinensis via transcriptomics and metabolomics.BMC plant biology · 2025Article
- In Vitro Evaluation of the Healing Potential and Proteomic Study ofMolecules (Basel, Switzerland) · 2025Article
- The role of the tumor microenvironment in HNSCC resistance and targeted therapy.Frontiers in immunology · 2025Review
- Bidirectional regulation of lipid metabolism and the tumor microenvironment: new perspectives from mechanism to therapy.Frontiers in immunology · 2025Review
- The contribution of mitochondria-associated ER membranes to cholesterol homeostasis.bioRxiv : the preprint server for biology · 2024Article
- Article
- Role of Squalene Epoxidase Gene (Journal of fungi (Basel, Switzerland) · 2024Article
- Exogenous ethephon treatment on the biosynthesis and accumulation of astragaloside IV in Astragalus membranaceus Bge. Var. Mongholicus (Bge.) Hsiao.Botanical studies · 2024Article
- A cytochrome P450 CYP87A4 imparts sterol side-chain cleavage in digoxin biosynthesis.Nature communications · 2023Article
- Repurposing antifungal drugs for cancer therapy.Journal of advanced research · 2023Review
- Targeting Microglial Metabolic Rewiring Synergizes with Immune-Checkpoint Blockade Therapy for Glioblastoma.Cancer discovery · 2023Article
- Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.eLife · 2023Article
- Lipid saturation induces degradation of squalene epoxidase for sterol homeostasis and cell survival.Life science alliance · 2023Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cholesterol biosynthesis is a high-cost process and, therefore, tightly regulated by both transcriptional and posttranslational negative feedback mechanisms in response to the level of cellular cholesterol. Squalene monooxygenase (SM, also known as squalene epoxidase or SQLE) is a rate-limiting enzyme in the cholesterol biosynthetic pathway and catalyzes epoxidation of squalene. The stability of SM is negatively regulated by cholesterol via its N-terminal regulatory domain (SM-N100). In this study, using a SM-luciferase fusion reporter cell line, we performed a chemical genetics screen that identified inhibitors of SM itself as up-regulators of SM. This effect was mediated through the SM-N100 region, competed with cholesterol-accelerated degradation, and required the E3 ubiquitin ligase MARCH6. However, up-regulation was not observed with statins, well-established cholesterol biosynthesis inhibitors, and this pointed to the presence of another mechanism other than reduced cholesterol synthesis. Further analyses revealed that squalene accumulation upon treatment with the SM inhibitor was responsible for the up-regulatory effect. Using photoaffinity labeling, we demonstrated that squalene directly bound to the N100 region, thereby reducing interaction with and ubiquitination by MARCH6. Our findings suggest that SM senses squalene via its N100 domain to increase its metabolic capacity, highlighting squalene as a feedforward factor for the cholesterol biosynthetic pathway.
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