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

Research output: Contribution to journalArticle

18 Citations (Scopus)

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

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Sumoylation
Mevalonic Acid
Enzymes
Ubiquinone
Ubiquitin
Hydroxymethylglutaryl-CoA Synthase
Cholesterol
Terpenes
Caenorhabditis elegans
Sterols
Proteasome Endopeptidase Complex
Metabolic Networks and Pathways
Eukaryota
Proteomics
Mitochondria
Cytoplasm
Homeostasis
Peptide Hydrolases
Pathology
Neoplasms

ASJC Scopus subject areas

  • General

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Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging. / Sapir, Amir; Tsur, Assaf; Koorman, Thijs; Ching, Kaitlin; Mishra, Prashant; Bardenheier, Annabelle; Podolsky, Lisa; Bening-Abu-Shach, Ulrike; Boxem, Mike; Chou, Tsui Fen; Broday, Limor; Sternberg, Paul W.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 37, 16.09.2014, p. E3880-E3889.

Research output: Contribution to journalArticle

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 2014, 'Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 37, pp. E3880-E3889. https://doi.org/10.1073/pnas.1414748111
Sapir, Amir ; Tsur, Assaf ; Koorman, Thijs ; Ching, Kaitlin ; Mishra, Prashant ; Bardenheier, Annabelle ; Podolsky, Lisa ; Bening-Abu-Shach, Ulrike ; Boxem, Mike ; Chou, Tsui Fen ; Broday, Limor ; Sternberg, Paul W. / Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 37. pp. E3880-E3889.
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