ArticleThe Journal of biological chemistry2019
Non-canonical ubiquitination of the cholesterol-regulated degron of squalene monooxygenase.
Article in The Journal of biological chemistry, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Squalene Epoxidase: Its Regulations and Links with Cancers.International journal of molecular sciences · 2024Pooled it
- Low temperature rather than hypoxia drives cholesterol synthesis and oxygen consumption in plateau zokors.iScience · 2026Article
- The role of ER-associated degradation and ER-phagy in health and disease.Signal transduction and targeted therapy · 2026Review
- UBE2J2 sensitizes the ERAD ubiquitination cascade to changes in membrane lipid saturation.Nature communications · 2025Article
- Determinants of chemoselectivity in ubiquitination by the J2 family of ubiquitin-conjugating enzymes.The EMBO journal · 2024Article
- Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE.Nature communications · 2024Article
- Polyphenols alleviate metabolic disorders: the role of ubiquitin-proteasome system.Frontiers in nutrition · 2024Review
- Decoding the crosstalk between mevalonate metabolism and T cell function.Immunological reviews · 2023Review
- The Brucella abortus Type IV Effector BspA Inhibits MARCH6-Dependent ERAD To Promote Intracellular Growth.Infection and immunity · 2023Article
- Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.eLife · 2023Article
- Deciphering non-canonical ubiquitin signaling: biology and methodology.Frontiers in molecular biosciences · 2023Review
- Lipid saturation induces degradation of squalene epoxidase for sterol homeostasis and cell survival.Life science alliance · 2023Article
- Thioester and Oxyester Linkages in the Ubiquitin System.Methods in molecular biology (Clifton, N.J.) · 2023Review
- Non-lysine ubiquitylation: Doing things differently.Frontiers in molecular biosciences · 2022Review
- Targeting the key cholesterol biosynthesis enzyme squalene monooxygenasefor cancer therapy.Frontiers in oncology · 2022Review
- The Targeting of Native Proteins to the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway: An Expanding Repertoire of Regulated Substrates.Biomolecules · 2021Review
- How Is the Fidelity of Proteins Ensured in Terms of Both Quality and Quantity at the Endoplasmic Reticulum? Mechanistic Insights into E3 Ubiquitin Ligases.International journal of molecular sciences · 2021Review
- The Degron Architecture of Squalene Monooxygenase and How Specific Lipids Calibrate Levels of This Key Cholesterol Synthesis Enzyme.Advances in experimental medicine and biology · 2021Article
- Post-translational control of the long and winding road to cholesterol.The Journal of biological chemistry · 2020Review
- High-throughput matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry-based deubiquitylating enzyme assay for drug discovery.Nature protocols · 2020Article
Corrections and comments
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Authors and funding
3 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Squalene monooxygenase (SM) is a rate-limiting enzyme in cholesterol synthesis. The region comprising the first 100 amino acids, termed SM N100, represents the shortest cholesterol-responsive degron and enables SM to sense excess cholesterol in the endoplasmic reticulum (ER) membrane. Cholesterol accelerates the ubiquitination of SM by membrane-associated ring-CH type finger 6 (MARCH6), a key E3 ubiquitin ligase involved in ER-associated degradation. However, the ubiquitination site required for cholesterol regulation of SM N100 is unknown. Here, we used SM N100 fused to GFP as a model degron to recapitulate cholesterol-mediated SM degradation and show that neither SM lysine residues nor the N terminus impart instability. Instead, we discovered four serines (Ser-59, Ser-61, Ser-83, and Ser-87) that are critical for cholesterol-accelerated degradation, with MS analysis confirming Ser-83 as a ubiquitination site. Notably, these two clusters of closely spaced serine residues are located in disordered domains flanking a 12-amino acid-long amphipathic helix (residues Gln-62-Leu-73) that together confer cholesterol responsiveness. In summary, our findings reveal the degron architecture of SM N100, introducing the role of non-canonical ubiquitination sites and deepening our molecular understanding of how SM is degraded in response to cholesterol.
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