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

• Published in: eLife Vol. 4
• Main Authors: Schumacher, Marc M, Elsabrouty, Rania, Seemann, Joachim, Jo, Youngah, DeBose-Boyd, Russell A
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 05.03.2015; eLife Sciences Publications, Ltd
• Subjects: Amino Acid Sequence; Biochemistry; Cell Biology; Cell Line; Cholesterol; Cholesterol - biosynthesis; cholesterol metabolism; Cornea; Corneal Dystrophies, Hereditary - genetics; Corneal Dystrophies, Hereditary - metabolism; Corneal dystrophy; CRISPR; Dimethylallyltranstransferase - genetics; Dimethylallyltranstransferase - metabolism; Diterpenes - pharmacology; Dystrophy; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum-Associated Degradation - drug effects; Endoplasmic Reticulum-Associated Degradation - genetics; Enzymes; ER associated degradation; Fractions; Golgi apparatus; Golgi Apparatus - metabolism; HEK293 Cells; Hereditary diseases; Humans; Hydroxymethylglutaryl CoA Reductases - genetics; Hydroxymethylglutaryl CoA Reductases - metabolism; Hydroxymethylglutaryl-CoA reductase; Immunoblotting; Immunoglobulins; isoprenoid; Menaquinones; Metabolism; Microscopy, Fluorescence; Molecular Sequence Data; Mutation; Pathogenesis; prenyltransferase; Protein Binding - drug effects; Protein Transport - drug effects; Regulation; RNA Interference; Sterols; Sterols - pharmacology; Surgery; Transplants & implants; vitamin K; cell biology; cholesterol metabolism; biochemistry; ER associated degradation; human; prenyltransferase; vitamin K; isoprenoid
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.05560

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. People with a rare genetic disorder called ‘Schnyder corneal dystrophy’ gradually lose their vision, because their corneas become increasingly cloudy. This cloudiness is caused by a build-up of excessive amounts of cholesterol, and the disorder itself is caused by mutations in a gene that encodes a protein called UBIAD1. Researchers have previously discovered that the UBIAD1 protein is involved in making vitamin K2, but it is not clear how this protein also helps to control cholesterol levels in the cornea. An enzyme called HMG CoA reductase makes a molecule that is used to make cholesterol and many other similar sterol molecules. A ‘feedback loop’ operates in cells to control the amount of the reductase and prevent cholesterol from becoming too high or too low. Sterol molecules, together with another molecule called geranylgeraniol, participate in this feedback loop by promoting the destruction of the reductase enzyme. Here, Schumacher et al. reveal a link between UBIAD1 and the reductase that may explain how UBIAD1 contributes to the production of excess cholesterol in patients with Schnyder corneal dystrophy. The experiments show that, in the presence of sterol molecules, UBIAD1 can bind to HMG CoA reductase to protect the reductase from being destroyed by other proteins. Geranylgeraniol—which stops the UBIAD1 protein from binding to the enzyme—is required to completely destroy the reductase enzyme. However, when UBIAD1 is missing, the reductase enzyme is destroyed even in the absence of geranylgeraniol. Furthermore, the experiments show that the genetic mutations linked to Schnyder corneal dystrophy lead to the production of versions of the UBIAD1 protein that bind to the reductase enzyme even when geranylgeraniol molecules are present. This prevents the normal breakdown of the reductase enzyme, which could lead to the build up of cholesterol in the cornea of individuals with the disorder. Schumacher et al.'s findings show that the UBIAD1 protein helps to control the levels of cholesterol in cells by protecting the HMG CoA reductase enzyme from destruction. These findings may aid the development of new therapies to lower cholesterol levels in cells, which may help patients with Schnyder's corneal dystrophy and other conditions caused by high cholesterol levels.