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Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):E3880-9. doi: 10.1073/pnas.1414748111. Epub 2014 Sep 3.

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

Author information

1
Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125;
2
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel;
3
Developmental Biology, Utrecht University, 3584 CH, Utrecht, The Netherlands; and.
4
Division of Biology and Biological Engineering and.
5
Division of Medical Genetics, Department of Pediatrics, and Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center, Torrance, CA 90502.
6
Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel; pws@caltech.edu broday@post.tau.ac.il.
7
Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91125; pws@caltech.edu broday@post.tau.ac.il.

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.

KEYWORDS:

HMG-CoA synthase; sterol synthesis; yeast two-hybrid

PMID:
25187565
PMCID:
PMC4169931
DOI:
10.1073/pnas.1414748111
[Indexed for MEDLINE]
Free PMC Article

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