Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging

Amir Sapir, Assaf Tsur, Thijs Koorman, Kaitlin Ching, Prashant Mishra, Annabelle Bardenheier, Lisa Podolsky, Ulrike Bening-Abu-Shach, Mike Boxem, Tsui Fen Chou, Limor Broday*, Paul W. Sternberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish
Pages (from-to)E3880-E3889
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number37
DOIs
StatePublished - 16 Sep 2014

Funding

FundersFunder number
Howard Hughes Medical InstitutePG -11-3086
Israel Science FoundationISF 1617/11

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