A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.

Acknowledgements: We thank all members of the Nathan lab for their helpful comments on the manuscript. We also thank Richard Stopforth for help with the LC-MS analysis. This work was supported by a Wellcome Senior Clinical Research Fellowship to J.A.N. (215477/Z/19/Z), an MRC project grant (MR/X008118/1) to J.A.N., a Lister Institute Research Fellowship to J.A.N., an MRC PhD studentship to A.S.D., a Pfizer ITEN award to J.A.N., a Wellcome Trust Principal Research Fellowship to P.J.L. (210688/Z/18/Z), an MRC project grant (MR/V011561/1) to P.J.L., a Wellcome Investigator Award to A.K. (222497/Z/21/Z), a National Institutes of Health (NIH) grant R01CA201276 to D.V. This work was also supported by the NIHR BRC.Funder: Lister Institute of Preventive Medicine; doi: https://doi.org/10.13039/501100001255Cholesterol 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.Lister Institute of Preventative Medicine National Institutes of Health (NIH) grant Pfizer ITEN Awar