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The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6

Scott, Nicola A., Sharpe, Laura J., Capell-Hattam, Isabelle M., Gullo, Samuel J., Luu, Winnie, Brown, Andrew J.·2020·Biochemical Journal
DOI 10.1042/bcj20190647PMC PMC6993871
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Abstract

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.

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Metadata

Authors
Scott, N. A., Sharpe, L. J., Capell-Hattam, I. M., Gullo, S. J., Luu, W., & Brown, A. J.
Affiliations
School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, New South Wales 2052, Australia
ORCID
Brown, Andrew J.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2020-01-31
Volume
477
Issue
2
Pages
541-555
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bcj20190647
PMC
PMC6993871
Cited by
31
References
4
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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