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