Cited by 205Ubiquitin and proteasome pathwaysCholesterol and Lipid MetabolismCancer, Lipids, and Metabolism

Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4

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Foresti, Ombretta, Ruggiano, Annamaria, Hannibal-Bach, Hans K, Ejsing, Christer S, Carvalho, Pedro·2013·eLife

Abstract

Sterol homeostasis is essential for the function of cellular membranes and requires feedback inhibition of HMGR, a rate-limiting enzyme of the mevalonate pathway. As HMGR acts at the beginning of the pathway, its regulation affects the synthesis of sterols and of other essential mevalonate-derived metabolites, such as ubiquinone or dolichol. Here, we describe a novel, evolutionarily conserved feedback system operating at a sterol-specific step of the mevalonate pathway. This involves the sterol-dependent degradation of squalene monooxygenase mediated by the yeast Doa10 or mammalian Teb4, a ubiquitin ligase implicated in a branch of the endoplasmic reticulum (ER)-associated protein degradation (ERAD) pathway. Since the other branch of ERAD is required for HMGR regulation, our results reveal a fundamental role for ERAD in sterol homeostasis, with the two branches of this pathway acting together to control sterol biosynthesis at different levels and thereby allowing independent regulation of multiple products of the mevalonate pathway. DOI:http://dx.doi.org/10.7554/eLife.00953.001.

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Crossref · 10.7554/elife.00953

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  • The yeast squalene monooxygenase Erg1 is also degraded through the ERAD pathway via the ubiquitin ligase Doa10 when lanosterol concentrations increase, in order to prevent the accumulation of toxic sterol intermediates.

    “The yeast squalene monooxygenase Erg1 is also degraded through the ERAD pathway via the ubiquitin ligase Doa10 when lanosterol concentrations increase, in order to prevent the accumulation of toxic sterol intermediates (Figure 1) [65].”
  • Subsequent lanosterol accumulation may inhibit Erg1.

    “the subsequent lanosterol accumulation may inhibit Erg1 [9,65].”
  • Erg11 function likely decreases due to the drop in heme levels when iron is scarce.

    “Erg11 function is likely to decrease due to the drop in heme levels that occurs when iron is scarce”

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Authors
Foresti, O., Ruggiano, A., Hannibal-Bach, H. K., Ejsing, C. S., & Carvalho, P.
Affiliations
  • Universitat Pompeu Fabra (ES)
  • Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark
  • University of Southern Denmark (DK)
Corresponding author
Carvalho, Pedro
Venue
eLife
Published
2013-07-23
Volume
2
Pages
e00953-e00953
ISSN
2050-084X (ISSN-L)
OpenAlex
W2136018257
Cited by
205
References
49
Citations by year
2026: 8 · 2025: 8 · 2024: 18 · 2023: 21 · 2022: 20 · 2021: 18 · 2020: 22 · 2019: 14 · 2018: 18 · 2017: 6 · 2016: 17 · 2015: 15 · 2014: 19 · 2013: 1
FWCI
7.72
Type
journal article
Language
en
Open access
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
  • University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, cc-by)
Funders
  • Center for Genomic Regulation (CRG)
  • Spanish MCCIN
  • International Early Career Scientist, Howard Hughes Medical Institute
  • Danish Council for Independent Research/Natural Sciences
  • Lundbeckfonden
  • La Caixa Graduate fellowship
  • Howard Hughes Medical Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
sterol homeostasis, squalene monooxygenase, Doa10, ubiquitin ligase, ER-associated degradation, mevalonate pathway, sterol biosynthesis, coenzyme Q10, dolichol, yeast, mammalian cells
MeSH terms
Homeostasis, Humans, Sterols, Substrate Specificity, Ubiquitin-Protein Ligases, Squalene Monooxygenase, Proteolysis

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