TY - JOUR TI - Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase AU - Coates, Hudson W AU - Capell-Hattam, Isabelle M AU - Olzomer, Ellen M AU - Du, Ximing AU - Farrell, Rhonda AU - Yang, Hongyuan AU - Byrne, Frances L AU - Brown, Andrew J A2 - Radhakrishnan, Arun A2 - Ron, David VL - 12 PY - 2023 DA - 2023/01/19 SP - e82843 C1 - eLife 2023;12:e82843 DO - 10.7554/eLife.82843 UR - https://doi.org/10.7554/eLife.82843 AB - 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-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a 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. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties. KW - Squalene monooxygenase KW - Cholesterol KW - Hypoxia KW - proteasome KW - protein degradation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -