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The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase

Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K(2). Here, we show that sterols s...

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Autores principales: Schumacher, Marc M, Elsabrouty, Rania, Seemann, Joachim, Jo, Youngah, DeBose-Boyd, Russell A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374513/
https://www.ncbi.nlm.nih.gov/pubmed/25742604
http://dx.doi.org/10.7554/eLife.05560
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author Schumacher, Marc M
Elsabrouty, Rania
Seemann, Joachim
Jo, Youngah
DeBose-Boyd, Russell A
author_facet Schumacher, Marc M
Elsabrouty, Rania
Seemann, Joachim
Jo, Youngah
DeBose-Boyd, Russell A
author_sort Schumacher, Marc M
collection PubMed
description Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K(2). Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD. DOI: http://dx.doi.org/10.7554/eLife.05560.001
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spelling pubmed-43745132015-03-27 The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase Schumacher, Marc M Elsabrouty, Rania Seemann, Joachim Jo, Youngah DeBose-Boyd, Russell A eLife Biochemistry Schnyder corneal dystrophy (SCD) is an autosomal dominant disorder in humans characterized by abnormal accumulation of cholesterol in the cornea. SCD-associated mutations have been identified in the gene encoding UBIAD1, a prenyltransferase that synthesizes vitamin K(2). Here, we show that sterols stimulate binding of UBIAD1 to the cholesterol biosynthetic enzyme HMG CoA reductase, which is subject to sterol-accelerated, endoplasmic reticulum (ER)-associated degradation augmented by the nonsterol isoprenoid geranylgeraniol through an unknown mechanism. Geranylgeraniol inhibits binding of UBIAD1 to reductase, allowing its degradation and promoting transport of UBIAD1 from the ER to the Golgi. CRISPR-CAS9-mediated knockout of UBIAD1 relieves the geranylgeraniol requirement for reductase degradation. SCD-associated mutations in UBIAD1 block its displacement from reductase in the presence of geranylgeraniol, thereby preventing degradation of reductase. The current results identify UBIAD1 as the elusive target of geranylgeraniol in reductase degradation, the inhibition of which may contribute to accumulation of cholesterol in SCD. DOI: http://dx.doi.org/10.7554/eLife.05560.001 eLife Sciences Publications, Ltd 2015-03-05 /pmc/articles/PMC4374513/ /pubmed/25742604 http://dx.doi.org/10.7554/eLife.05560 Text en © 2015, Schumacher et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Biochemistry
Schumacher, Marc M
Elsabrouty, Rania
Seemann, Joachim
Jo, Youngah
DeBose-Boyd, Russell A
The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
title The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
title_full The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
title_fullStr The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
title_full_unstemmed The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
title_short The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
title_sort prenyltransferase ubiad1 is the target of geranylgeraniol in degradation of hmg coa reductase
topic Biochemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4374513/
https://www.ncbi.nlm.nih.gov/pubmed/25742604
http://dx.doi.org/10.7554/eLife.05560
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