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

ELife
Marc M SchumacherRussell A DeBose-Boyd

Abstract

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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Citations

Jun 15, 2016·Annual Review of Nutrition·Julian StevensonJames A Olzmann
Oct 25, 2016·Trends in Cell Biology·Dae In Kim, Kyle J Roux
Apr 29, 2016·Journal of Lipid Research·Marc M SchumacherRussell A DeBose-Boyd
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Aug 11, 2021·Angewandte Chemie·Yasushi TakemotoMotonari Uesugi
Aug 10, 2021·Molecular Medicine Reports·Jumin Xie, Lingxing Li

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
light scattering
co-immunoprecipitation
ubiquitination
immunoprecipitation
FCS
affinity purification
transfection
PCR
immunoprecipitations

Software Mentioned

Openlab
ImageJ

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