# Examining Mechanism and Physiological Significance of HMG CoA Reductase ER-Associated Degradation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $429,300

## Abstract

Project Summary
Multiple feedback mechanisms converge on the polytopic, ER (endoplasmic reticulum)-localized enzyme HMG
CoA reductase (HMGCR), which catalyzes a key step in synthesis of cholesterol and essential nonsterol
isoprenoids including Fpp (farnesyl pyrophosphate) and GGpp (geranylgeranyl pyrophosphate). Fpp and GGpp
can become attached to many cellular proteins and are utilized in synthesis of dolichol, ubiquinone, heme, and
vitamin K2. One mechanism for feedback control of HMGCR involves sterol-induced ubiquitination, which marks
the enzyme for extraction across ER membranes and subsequent release into the cytosol for proteasome-
mediated ERAD (ER-associated degradation). GGpp augments ERAD of HMGCR by enhancing its membrane
extraction. We recently discovered that GGpp inhibits sterol-induced binding of HMGCR to UBIAD1 (UbiA
prenyltransferase domain-containing protein-1), which utilizes GGpp to synthesize vitamin K2. This inhibition
allows for membrane extraction of HMGCR and ER-to-Golgi transport of UBIAD1. Mutations in UBIAD1 cause
SCD (Schnyder corneal dystrophy), an autosomal dominant eye disease characterized by corneal accumulation
of cholesterol. SCD-associated UBIAD1 resists GGpp-induced release from HMGCR and becomes trapped in
the ER where it blocks HMGCR ERAD.
Building on discoveries summarized above, we are now poised to 1) elucidate mechanisms through which
sterols promote ubiquitination of HMGCR; 2) determine the molecular structure of HMGCR; 3) establish
how ubiquitinated HMGCR is removed from ER membranes for ERAD; and 4) ascertain the physiological
significance of HMGCR ERAD. Collectively, these studies will provide key information regarding mechanisms
by which polytopic HMGCR is removed from ER membranes and delivered cytosolic proteasomes for ERAD. In
addition, these studies have significant clinical implications. HMGCR is the target of statins, widely prescribed
drugs that lower plasma LDL-cholesterol and reduce cardiovascular disease. However, statins trigger responses
that cause accumulation of HMGCR, which blunts their clinical effects. This increase results in part, from slowed
ERAD of HMGCR. Thus, elucidating mechanisms for HMGCR ERAD holds promise for development of new
therapies that increase the efficacy of statins and further reduce heart attacks.

## Key facts

- **NIH application ID:** 9978121
- **Project number:** 5R01GM134700-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Russell Alfred DeBose-Boyd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $429,300
- **Award type:** 5
- **Project period:** 2019-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978121

## Citation

> US National Institutes of Health, RePORTER application 9978121, Examining Mechanism and Physiological Significance of HMG CoA Reductase ER-Associated Degradation (5R01GM134700-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9978121. Licensed CC0.

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