Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4
Open accessAbstract
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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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].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [65]
Subsequent lanosterol accumulation may inhibit Erg1.
“the subsequent lanosterol accumulation may inhibit Erg1 [9,65].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [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”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [65]
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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
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2013-07-23
- Volume
- 2
- Pages
- e00953-e00953
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC3721249
- 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
- gold
- doi.org
- Licence
- 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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