A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis

Anna S. Dickson, Tekle Pauzaite, Esther Arnaiz, Brian M. Ortmann, James A. West, Norbert Volkmar, Anthony W. Martinelli, Zhaoqi Li, Niek Wit, Dennis Vitkup, Arthur Kaser, Paul J. Lehner and James A. Nathan ()
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Anna S. Dickson: University of Cambridge
Tekle Pauzaite: University of Cambridge
Esther Arnaiz: University of Cambridge
Brian M. Ortmann: University of Cambridge
James A. West: University of Cambridge
Norbert Volkmar: University of Cambridge
Anthony W. Martinelli: University of Cambridge
Zhaoqi Li: Massachusetts Institute of Technology
Niek Wit: University of Cambridge
Dennis Vitkup: Columbia University
Arthur Kaser: University of Cambridge
Paul J. Lehner: University of Cambridge
James A. Nathan: University of Cambridge

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.

Date: 2023
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DOI: 10.1038/s41467-023-40541-1

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