# Geranylgeranyl-Mediated Regulation of Prenyltransferase UBIAD1:  A Sensing Mechanism Controlling HMG CoA Reductase

> **NIH NIH P01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $583,773

## Abstract

Schnyder corneal dystrophy (SCD) is a rare autosomal dominant eye disease characterized by
progressive opacification of the cornea, owing to abnormal accumulation of cholesterol. Mutations associated
with SCD have been identified in the gene encoding UBIAD1 (UbiA prenyltransferase domain-containing
protein-1), which utilizes the nonsterol isoprenoid GGpp (geranylgeranyl pyrophosphate) to synthesize vitamin
K2. Our preliminary studies reveal that sterols trigger binding of UBIAD1 to the ER (endoplasmic reticulum)-
localized enzyme HMG CoA reductase. The reductase produces mevalonate, an important intermediate in
synthesis of cholesterol and nonsterol isoprenoids such as ubiquinone, vitamin K2, dolichol, and the farnesyl
and geranylgeranyl groups that are attached to many cellular proteins. Sterol-regulated ubiquitination is
obligatory for ERAD (ER-associated degradation) of reductase. GGpp inhibits binding of UBIAD1 to reductase,
which allows for maximal ERAD of reductase and ER-to-Golgi transport of UBIAD1. Eliminating UBIAD1
relieves the GGpp requirement for reductase ERAD, indicating the reaction is inhibited by the prenyltransferase.
SCD-associated mutants of UBIAD1 resist GGpp-induced release from reductase and remain sequestered in
the ER where they block sterol-accelerated reductase ERAD.
 Building on these observations, we now propose studies to elucidate mechanisms through which GGpp
regulates intracellular trafficking of UBIAD1 and determine how this regulation impacts synthesis of vitamin K2
and cholesterol. To achieve this goal, we will pursue the following Specific Aims: 1) Elucidate mechanism
through which GGpp governs intracellular transport of UBIAD1; 2) Determine significance of the ER-to-
Golgi transport of UBIAD1; and 3) Examine role for UBIAD1 as a membrane sensor of GGpp. Collectively,
the results of these studies will explain how intracellular transport of UBIAD1 controls reductase ERAD so as
to permit continuous synthesis of essential nonsterol isoprenoids in sterol-replete cells. Insight into mechanisms
for reductase ERAD may lead to therapeutic interventions that retard or prevent corneal accumulation of
cholesterol associated with Schnyder corneal dystrophy, highlighting the clinical significance of our proposed
studies.
C/PPG 2015 – RP2 – 30-line Summary

## Key facts

- **NIH application ID:** 9940758
- **Project number:** 5P01HL020948-44
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Russell Alfred DeBose-Boyd
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $583,773
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940758

## Citation

> US National Institutes of Health, RePORTER application 9940758, Geranylgeranyl-Mediated Regulation of Prenyltransferase UBIAD1:  A Sensing Mechanism Controlling HMG CoA Reductase (5P01HL020948-44). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9940758. Licensed CC0.

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