ArticleProceedings of the National Academy of Sciences of the United States of America2014
Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging.
Article in Proceedings of the National Academy of Sciences of the United States of America, 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, 55 citations in OpenAlex.
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- lncRNA EBLN3P Promotes Proliferation, Metastasis and Stemness of Gastric Cancer Cells via miR-141-3p/HMGCS1.Biochemical genetics · 2026Article
- Prenols and prenoic acids in metabolism, disease, and aging.Journal of lipid research · 2026Review
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- Aging impairs the antiviral defense in Caenorhabditis elegans due to loss of DRH-1/RIG-I deSUMOylation by ULP-4/SENP7.EMBO reports · 2025Article
- HMGCS1 variants cause rigid spine syndrome amenable to mevalonic acid treatment in an animal model.Brain : a journal of neurology · 2025Article
- SUMO-mediated regulation of H3K4me3 reader SET-26 controls germline development in C. elegans.PLoS biology · 2025Article
- Histone β-hydroxybutyrylation is critical in reversal of sarcopenia.Aging cell · 2024Article
- FOXA3 regulates cholesterol metabolism to compensate for low uptake during the progression of lung adenocarcinoma.PLoS biology · 2024Article
- ULP-2 SUMO protease regulates UPRFree radical biology & medicine · 2024Article
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- ERRα Up-Regulates Invadopodia Formation by Targeting HMGCS1 to Promote Endometrial Cancer Invasion and Metastasis.International journal of molecular sciences · 2023Article
- Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer.Sub-cellular biochemistry · 2022Article
- Proteo-transcriptomics meta-analysis identifies SUMO2 as a promising target in glioblastoma multiforme therapeutics.Cancer cell international · 2021Article
- SUMO modification in apoptosis.Journal of molecular histology · 2021Review
- Beyond Proteostasis: Lipid Metabolism as a New Player in ER Homeostasis.Metabolites · 2021Review
- Coordinate Regulation of Ribosome and tRNA Biogenesis Controls Hypoxic Injury and Translation.Current biology : CB · 2021Article
- Post-translational control of the long and winding road to cholesterol.The Journal of biological chemistry · 2020Review
- Not So Slim Anymore-Evidence for the Role of SUMO in the Regulation of Lipid Metabolism.Biomolecules · 2020Review
- Article
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Authors and funding
12 authors at 5 institutions in 3 countries.
Funding
Abstract
Many metabolic pathways are critically regulated during development and aging but little is known about the molecular mechanisms underlying this regulation. One key metabolic cascade in eukaryotes is the mevalonate pathway. It catalyzes the synthesis of sterol and nonsterol isoprenoids, such as cholesterol and ubiquinone, as well as other metabolites. In humans, an age-dependent decrease in ubiquinone levels and changes in cholesterol homeostasis suggest that mevalonate pathway activity changes with age. However, our knowledge of the mechanistic basis of these changes remains rudimentary. We have identified a regulatory circuit controlling the sumoylation state of Caenorhabditis elegans HMG-CoA synthase (HMGS-1). This protein is the ortholog of human HMGCS1 enzyme, which mediates the first committed step of the mevalonate pathway. In vivo, HMGS-1 undergoes an age-dependent sumoylation that is balanced by the activity of ULP-4 small ubiquitin-like modifier protease. ULP-4 exhibits an age-regulated expression pattern and a dynamic cytoplasm-to-mitochondria translocation. Thus, spatiotemporal ULP-4 activity controls the HMGS-1 sumoylation state in a mechanism that orchestrates mevalonate pathway activity with the age of the organism. To expand the HMGS-1 regulatory network, we combined proteomic analyses with knockout studies and found that the HMGS-1 level is also governed by the ubiquitin-proteasome pathway. We propose that these conserved molecular circuits have evolved to govern the level of mevalonate pathway flux during aging, a flux whose dysregulation is associated with numerous age-dependent cardiovascular and cancer pathologies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.