Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase

Abstract

Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-requiring enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show that hypoxia is the physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6, and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. Truncation of SM permits its localization to lipid droplets and is increased in hypoxic endometrial cancer tissues. These results uncover a feedforward mechanism that enables SM to accommodate fluctuations in substrate levels yet is also a likely contributor to its widely reported oncogenic properties.