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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eLife Sciences Publications Ltd
2015-03-01
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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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language | English |
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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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