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.

中文翻译：

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哺乳动物胆固醇合成酶角鲨烯单加氧酶被蛋白酶截短化为组成型活性形式

角鲨烯单加氧酶（SM）是胆固醇合成的限速酶，在多种癌症类型中均具有致癌性。SM通过胆固醇诱导的降解进行反馈调节，这取决于其脂质敏感的N末端调节域。在这里，我们表征了SM的内源性截短形式，并表明它是抗胆固醇的，因此具有组成性活性。SM的截断在其内质网相关降解期间发生，并且需要蛋白酶体，其部分降解SM N端并消除该区域内的胆固醇敏感元件。使用诱变研究，我们证明SM的部分降解取决于截短位点附近的固有无序区域和相邻催化结构域的稳定性。最后，截短可将SM从整合蛋白转化为周围ER膜蛋白。这些发现揭示了胆固醇合成的细胞控制中的另一层复杂性，并将SM确立为已知经历蛋白酶体截短的第一个真核酶。