Cambridge Institute of Therapeutic Immunology & Infectious Disease (CITIID), Jeffrey Cheah Biomedical Centre, Department of Medicine, University of Cambridge, Cambridge, CB2 0AW, UK.
Ochre-Bio Ltd, Hayakawa Building, Oxford Science Park, Edmund Halley Road, Oxford, OX4 4GB, UK.
Nat Commun. 2023 Aug 9;14(1):4816. doi: 10.1038/s41467-023-40541-1.
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.
胆固醇生物合成是一个高度调控的、依赖氧的途径，对细胞膜的完整性和生长至关重要。在真菌中，对氧产生固醇的依赖性导致了一个共享的转录反应，类似于后生动物中脯氨酰羟化酶对缺氧诱导因子（HIFs）的作用。是否存在类似的后生动物途径尚不清楚。在这里，我们确定甾醇调节元件结合蛋白 2（SREBP2），即驱动哺乳动物固醇产生的关键转录因子，是胆固醇合成的氧敏感调节剂。在低氧条件下 SREBP2 的降解会破坏正常的固醇感应反应，且不依赖于 HIF。我们通过鉴定 MARCHF6，发现它在低氧条件下通过 NADPH 介导的激活，是控制 SREBP2 稳定性的主要泛素连接酶。低氧介导的 SREBP2 降解通过迫使细胞依赖外源性胆固醇摄取来保护细胞免受他汀类药物诱导的细胞死亡，解释了为什么许多实体器官肿瘤对胆固醇成为营养缺陷型。因此，我们的研究结果揭示了一种通过受调控的 SREBP2 依赖性蛋白降解来调节胆固醇合成的氧敏感途径。
