The mammalian cholesterol synthesis enzyme squalene monooxygenase is proteasomally truncated to a constitutively active form

Squalene monooxygenase (SM) is a rate-limiting enzyme of cholesterol synthesis that is oncogenic in a range of cancer types. SM is subject to feedback regulation via cholesterol-induced degradation, which depends on its lipid-sensing N terminal regulatory domain. Here, we characterize an endogenous truncated form of SM and show that it is cholesterol-resistant, and therefore constitutively active. Truncation of SM occurs during its endoplasmic reticulum-associated degradation and requires the proteasome, which partially degrades the SM N-terminus and eliminates cholesterol-sensing elements within this region. Using mutagenesis studies, we demonstrate that partial degradation of SM depends on both an intrinsically disordered region near the truncation site and the stability of the adjacent catalytic domain. Finally, truncation converts SM from an integral to a peripheral ER membrane protein. These findings uncover an additional layer of complexity in the cellular control of cholesterol synthesis and establish SM as the first eukaryotic enzyme known to undergo proteasomal truncation.