title: Cholesterol-dependent degradation of squalene monooxygenase, a control point in cholesterol synthesis beyond HMG-CoA reductase.
abstract: 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 in 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 possible control point in cholesterol synthesis.
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia.
authors.forename: Saloni
authors.initials: S
authors.lastname: Gill
authors.forename: Julian
authors.initials: J
authors.lastname: Stevenson
authors.forename: Ika
authors.initials: I
authors.lastname: Kristiana
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brown
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013185:Squalene / Q000378:metabolism; D050603:Squalene Monooxygenase / Q000737:chemistry / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D013185:Squalene; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D050603:Squalene Monooxygenase; D046988:Proteasome Endopeptidase Complex