# Mechanism and Significance of HMG Co-A Synthase 1 Degradation

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $369,600

## Abstract

Abstract
The mevalonate pathway enzymes produce precursors of sterols and isoprenoids, essential metabolites for cell
signaling and membrane biogenesis. As such, cells employ complex transcriptional, translational, and post-
translational processes to regulate mevalonate production. Specifically, the ubiquitin proteasome system (UPS)
tightly controls the mevalonate enzymes on the ER membrane, converging on the ER-associated degradation
pathway. Importantly, increased levels of distinct sterol metabolites in the ER membrane cause proteolysis of
specific enzymes, suggesting that the rate-liming enzyme in the mevalonate pathway can change based on the
stimuli. While studies have focused on the feedback regulation of the mevalonate pathway enzymes upon sterol
stimulation, it is unclear whether other environmental changes, such as cell growth signaling or nutrient
availability, can also tightly control the mevalonate synthesis through post-translational mechanisms. Here, we
report that HMG-CoA Synthase1 (HMGCS1), the first committed enzyme in the mevalonate pathway, is the
primary responder of the master regulator of cell growth, mTORC1, among ~20 mevalonate/cholesterol
enzymes. Our quantitative degradomics data indicate that HMGCS1 is stable for several days in cells with active
mTORC1 while substantially degraded within 5 hours of mTOR inhibition. We have determined the E3 ligase
that is solely responsible for the degradation of HMGCS1. Reversing the stabilization of HMGCS1, by a targeted
proteolysis approach, significantly inhibited the anchorage-dependent and independent cell proliferation in
HMGCS1 copy-number-dependent manner. Altogether, our study suggests that HMGCS1 is an
underappreciated, first gatekeeper of the mevalonate pathway flux and that the mTORC1-UPS-HMGCS1 axis
dynamically controls the initiation of mevalonate production to meet the cellular metabolic demand. This pathway
is distinct from the ER-associated degradation of HMGCR and Squalene monooxygenase (SQLE), which
respond to cellular sterol levels.

## Key facts

- **NIH application ID:** 10882619
- **Project number:** 1R01GM152667-01A1
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Heeseon An
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $369,600
- **Award type:** 1
- **Project period:** 2024-05-07 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882619

## Citation

> US National Institutes of Health, RePORTER application 10882619, Mechanism and Significance of HMG Co-A Synthase 1 Degradation (1R01GM152667-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10882619. Licensed CC0.

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