The Degron Architecture of Squalene Monooxygenase and How Specific Lipids Calibrate Levels of This Key Cholesterol Synthesis Enzyme.

Cholesterol synthesis is a fundamental process that contributes to cellular cholesterol homeostasis. Cells execute transcriptional and post-translational mechanisms to control the abundance of enzymes of the cholesterol synthesis pathway, consequently affecting cholesterol production. One such highly tuned enzyme is squalene monooxygenase (SM), which catalyzes a rate-limiting step in the pathway. A well-characterized mechanism is the cholesterol-mediated degradation of SM. Notably, lipids (cholesterol, plasmalogens, squalene, and unsaturated fatty acids) can act as cellular signals that either promote or reduce SM degradation. The N-terminal region of SM consists of the shortest known cholesterol-responsive degron, characterized by atypical membrane anchoring structures, namely a re-entrant loop and an amphipathic helix. SM also undergoes non-canonical ubiquitination on serine, a relatively uncommon attachment site for ubiquitination. The structure of the catalytic domain of SM has been solved, providing insights into the catalytic mechanisms and modes of inhibition by well-known SM inhibitors, some of which have been effective in lowering cholesterol levels in animal models. Certain human cancers have been linked to dysregulation of SM levels and activity, further emphasizing the relevance of SM in health and disease.