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

Sapir, Amir and Tsur, Assaf and Koorman, Thijs and Ching, Kaitlin and Mishra, Prashant and Bardenheier, Annabelle and Podolsky, Lisa and Bening-Abu-Schach, Ulrike and Boxem, Mike and Chou, Tsui-Fen and Broday, Limor and Sternberg, Paul W. (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, 111 (37). E3880-E3889. ISSN 0027-8424. PMCID PMC4169931. doi:10.1073/pnas.1414748111.

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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.

Item Type:Article
Related URLs:
URLURL TypeDescription Information CentralArticle
Sapir, Amir0000-0001-9888-1800
Koorman, Thijs0000-0002-6064-3353
Ching, Kaitlin0000-0002-0517-2421
Boxem, Mike0000-0003-3966-4173
Chou, Tsui-Fen0000-0003-2410-2186
Sternberg, Paul W.0000-0002-7699-0173
Additional Information:© 2014 National Academy of Sciences. Contributed by Paul W. Sternberg, August 6, 2014 (sent for review July 3, 2014). Published online before print September 3, 2014, doi: 10.1073/pnas.1414748111. We thank Shohei Mitani for a knockout allele, Ann Wang for the ulp-4 RNAi in the ulp-4::gfp experiments, Adam Kolawa and Kevin Yu for their help with worm functional assays, Robyn Branicky and William Schafer for sharing the clh-3::mCherry worms, Brian Williams for total human RNA, David Chan for use of his Seahorse oxygen consumption analyzer, Domenico Fasci for his help with in vitro sumoylation assays, and Jennifer Watt for fat measurements. We also thank WormBase and the Caenorhabditis Genetics Center for C. elegans genetic annotation and strains. The Henry L. Guenther Foundation supported the Q-Exactive mass spectrometer. This research was supported by the Howard Hughes Medical Institute (of which P.W.S. is an Investigator), the Israel Cancer Research Fund PG -11-3086 (to L.B.), and Israel Science Foundation Grant ISF 1617/11 (to L.B.). A.T. was supported by the Ori Foundation-In Memory of Ori Levi, the Israeli Mitochondrial Disease Foundation ( T.-F.C. is a member of University of California, Los Angeles’s Jonsson Comprehensive Cancer Center. P.M. is supported by a Baxter Senior Postdoctoral Fellowship. Author contributions: A.S., M.B., T.-F.C., L.B., and P.W.S. designed research; A.S., A.T., T.K., K.C., P.M., A.B., L.P., U.B.-A.-S., T.-F.C., and L.B. performed research; A.S., A.T., T.K., P.M., M.B., T.-F.C., and L.B. analyzed data; and A.S., K.C., L.B., and P.W.S. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at
Funding AgencyGrant Number
Henry L. Guenther FoundationUNSPECIFIED
Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Israel Cancer Research FundPG-11-3086
Israel Science FoundationISF 1617/11
Israeli Mitochondrial Disease FoundationUNSPECIFIED
Baxter FoundationUNSPECIFIED
Subject Keywords:HMG-CoA synthase; sterol synthesis; yeast two-hybrid
Issue or Number:37
PubMed Central ID:PMC4169931
Record Number:CaltechAUTHORS:20140904-122954030
Persistent URL:
Official Citation: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, and Paul W. Sternberg Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging PNAS 2014 111 (37) E3880-E3889; published ahead of print September 3, 2014, doi:10.1073/pnas.1414748111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:49244
Deposited By: George Porter
Deposited On:04 Sep 2014 20:05
Last Modified:10 Nov 2021 18:41

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