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Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Capell-Hattam, Isabelle M 
Olzomer, Ellen M 
Farrell, Rhonda 

Abstract

Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.

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Keywords

Cholesterol, Hypoxia, Squalene monooxygenase, biochemistry, chemical biology, human, proteasome, protein degradation, Humans, Squalene Monooxygenase, Cholesterol, Squalene, Hypoxia, Oxygen

Journal Title

Elife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

12

Publisher

eLife Sciences Publications, Ltd