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Lookup NU author(s): Dr Brian OrtmannORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2023, Springer Nature Limited. 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.
Author(s): Dickson AS, Pauzaite T, Arnaiz E, Ortmann BM, West JA, Volkmar N, Martinelli AW, Li Z, Wit N, Vitkup D, Kaser A, Lehner PJ, Nathan JA
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2023
Volume: 14
Online publication date: 09/08/2023
Acceptance date: 30/07/2023
Date deposited: 14/03/2025
ISSN (electronic): 2041-1723
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41467-023-40541-1
DOI: 10.1038/s41467-023-40541-1
Data Access Statement: All data reported in this paper will be shared by the lead contact upon request. The code for the CRISPR screen pipeline analysis can be found at 10.5281/zenodo.8135219. Source data are provided with this paper. In addition, source data for the HMGCR-Clover screen is included in Supplementary Data, the SREBP2-Clover screen in Supplementary Data, and the LC-MS cholesterol analysis in Supplementary Date. Any additional information required to reanalyse the data reported in this paper is available from the lead contact upon request. Source data are provided with this paper.
PubMed id: 37558666
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