Controlled sumoylation of the mevalonate pathway enzyme HMGS-1 regulates metabolism during aging

Significance The mevalonate pathway plays a critical role in cholesterol homeostasis and cancer development, two major challenges in modern medicine. Consequently, cholesterol-reducing medications (statins) that target this pathway are the best-selling pharmaceutical drugs in history. Beyond regulation of the enzyme HMG-CoA reductase, little is known about additional posttranslational regulatory nodes in the mevalonate pathway or how this cascade is controlled with age. We have discovered a regulatory circuit that controls HMGS-1, the first enzyme of the mevalonate pathway, during aging. HMGS-1 is regulated by posttranslational ubiquitination and age-dependent sumoylation. Sumoylation is reversed by the spatiotemporally controlled activity of a specific small ubiquitin-like modifier protease. This conserved molecular circuit could serve as a handle for targeting the mevalonate pathway in future therapeutics.