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 K2. Here, we show that sterols sti...

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Main Authors: Marc M Schumacher, Rania Elsabrouty, Joachim Seemann, Youngah Jo, Russell A DeBose-Boyd
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2015-03-01
Series:eLife
Subjects:
Online Access:https://elifesciences.org/articles/05560
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author Marc M Schumacher
Rania Elsabrouty
Joachim Seemann
Youngah Jo
Russell A DeBose-Boyd
author_facet Marc M Schumacher
Rania Elsabrouty
Joachim Seemann
Youngah Jo
Russell A DeBose-Boyd
author_sort Marc M Schumacher
collection DOAJ
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 K2. 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.
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spelling doaj.art-c3285b90f6e44c008e47ea98244856c32022-12-22T03:52:13ZengeLife Sciences Publications LtdeLife2050-084X2015-03-01410.7554/eLife.05560The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductaseMarc M Schumacher0Rania Elsabrouty1Joachim Seemann2Youngah Jo3Russell A DeBose-Boyd4Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Cell Biology, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United StatesDepartment of Molecular Genetics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, United StatesSchnyder 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 K2. 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.https://elifesciences.org/articles/05560ER associated degradationcholesterol metabolismprenyltransferasevitamin Kisoprenoid
spellingShingle Marc M Schumacher
Rania Elsabrouty
Joachim Seemann
Youngah Jo
Russell A DeBose-Boyd
The prenyltransferase UBIAD1 is the target of geranylgeraniol in degradation of HMG CoA reductase
eLife
ER associated degradation
cholesterol metabolism
prenyltransferase
vitamin K
isoprenoid
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 ER associated degradation
cholesterol metabolism
prenyltransferase
vitamin K
isoprenoid
url https://elifesciences.org/articles/05560
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