RRC ID 45846
著者 Sapir A, Tsur A, Koorman T, Ching K, Mishra P, Bardenheier A, Podolsky L, Bening-Abu-Shach U, Boxem M, Chou TF, Broday L, Sternberg PW.
タイトル Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging.
ジャーナル Proc Natl Acad Sci U S A
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.
巻・号 111(37)
ページ E3880-9
公開日 2014-9-16
DOI 10.1073/pnas.1414748111
PII 1414748111
PMID 25187565
PMC PMC4169931
MeSH Aging / metabolism* Animals Caenorhabditis elegans / enzymology* Caenorhabditis elegans / physiology* Caenorhabditis elegans Proteins / metabolism* Cytosol / metabolism Humans Hydroxymethylglutaryl-CoA Synthase / physiology* Lysine / metabolism Metabolic Networks and Pathways* Mevalonic Acid / metabolism* Mitochondria / metabolism Models, Biological Mutation / genetics Phenotype Proteasome Endopeptidase Complex / metabolism Protein Binding Protein Interaction Maps Protein Transport Sumoylation* Ubiquitin / metabolism
IF 9.412
引用数 26
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
線虫 tm3688