Cholesterol‐Dependent Proteasomal Degradation of Squalene Monooxygenase, a Second Control Point in Cholesterol Synthesis

Exquisite control of cholesterol synthesis is crucial for maintaining homeostasis of this vital yet potentially toxic lipid. Squalene monooxygenase (SM) catalyzes the first oxygenation step in cholesterol synthesis, acting on squalene before cyclization into the basic steroid structure. Using model cell systems, we found that cholesterol caused the accumulation of the substrate squalene, suggesting that SM may serve as a flux‐controlling enzyme beyond 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGR, considered as rate‐limiting). Cholesterol accelerated the proteasomal degradation of SM which required the N‐terminal domain, partially conserved in vertebrates, but not lower organisms. Unlike HMGR, SM degradation is not mediated by Insig, 24,25‐dihydrolanosterol or side‐chain oxysterols, but rather by cholesterol itself. Importantly, SM's N‐terminal domain conferred cholesterol‐regulated turnover on heterologous fusion proteins. Furthermore, proteasomal inhibition almost totally eliminated squalene accumulation, highlighting the importance of this degradation mechanism for the control of SM, and suggesting this as a novel control point in cholesterol synthesis. The Brown Lab was supported by grants from the NHMRC (568619), PCFA (PR36), and UNSW Goldstar Award. Julian Stevenson is supported by an Australian Postgraduate Award.