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

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 ot...

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Autores principales: Scott, Nicola A., Sharpe, Laura J., Capell-Hattam, Isabelle M., Gullo, Samuel J., Luu, Winnie, Brown, Andrew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993871/
https://www.ncbi.nlm.nih.gov/pubmed/31904814
http://dx.doi.org/10.1042/BCJ20190647
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author Scott, Nicola A.
Sharpe, Laura J.
Capell-Hattam, Isabelle M.
Gullo, Samuel J.
Luu, Winnie
Brown, Andrew J.
author_facet Scott, Nicola A.
Sharpe, Laura J.
Capell-Hattam, Isabelle M.
Gullo, Samuel J.
Luu, Winnie
Brown, Andrew J.
author_sort Scott, Nicola A.
collection PubMed
description 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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spelling pubmed-69938712020-02-10 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. Biochem J Cell Homeostasis & Autophagy 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. Portland Press Ltd. 2020-01-31 2020-01-31 /pmc/articles/PMC6993871/ /pubmed/31904814 http://dx.doi.org/10.1042/BCJ20190647 Text en © 2020 The Author(s) https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . Open access for this article was enabled by the participation of University of New South Wales in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with CAUL.
spellingShingle Cell Homeostasis & Autophagy
Scott, Nicola A.
Sharpe, Laura J.
Capell-Hattam, Isabelle M.
Gullo, Samuel J.
Luu, Winnie
Brown, Andrew J.
The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
title The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
title_full The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
title_fullStr The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
title_full_unstemmed The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
title_short The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6
title_sort cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the e3 ubiquitin ligase march6
topic Cell Homeostasis & Autophagy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993871/
https://www.ncbi.nlm.nih.gov/pubmed/31904814
http://dx.doi.org/10.1042/BCJ20190647
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