The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
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- Nicola A. Scott
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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- Laura J. Sharpe
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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- Isabelle M. Capell-Hattam
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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- Samuel J. Gullo
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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- Winnie Luu
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
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- Andrew J. Brown
- School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
抄録
<jats:p>Cholesterol synthesis is a tightly controlled pathway, with over 20 enzymes involved. Each of these enzymes can be distinctly regulated, helping to fine-tune the production of cholesterol and its functional intermediates. Several enzymes are degraded in response to increased sterol levels, whilst others remain stable. We hypothesised that an enzyme at a key branch point in the pathway, lanosterol 14α-demethylase (LDM) may be post-translationally regulated. Here, we show that the preceding enzyme, lanosterol synthase is stable, whilst LDM is rapidly degraded. Surprisingly, this degradation is not triggered by sterols. However, the E3 ubiquitin ligase membrane-associated ring-CH-type finger 6 (MARCH6), known to control earlier rate-limiting steps in cholesterol synthesis, also control levels of LDM and the terminal cholesterol synthesis enzyme, 24-dehydrocholesterol reductase. Our work highlights MARCH6 as the first example of an E3 ubiquitin ligase that targets multiple steps in a biochemical pathway and indicates new facets in the control of cholesterol synthesis.</jats:p>
収録刊行物
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- Biochemical Journal
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Biochemical Journal 477 (2), 541-555, 2020-01-31
Portland Press Ltd.