Author Correction: A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis (Nature Communications, (2023), 14, 1, (4816), 10.1038/s41467-023-40541-1)

\ua9 The Author(s) 2024.The original version of this Article contained errors in Figs. 2, 3, and 5. In the original Fig. 2e, the flow cytometry panel on the right (labelled “StD (24 hr) followed by 1% O2 (~16 hr)”), was inadvertently duplicated from the panel on the left (labelled “Concurrent StD and 1% O2 (~24 hr)”). In the original Fig. 3a, the flow cytometry panel on the right (labelled “Roxadustat”), was inadvertently duplicated from the panel on the left (labelled “DMOG”). In the original Fig. 5c, the labels did not properly communicate that both panels come from the same experiment and have the same controls. The following sentence has been added to the end of the legend for Fig. 5c: “The data depicted in the left and right panels originated from the same experiment and as such the control plots are the same in both.” Figures 2, 3, and 5 have been corrected in both the PDF and HTML versions of the Article. The original version of the Supplementary Information associated with this Article contained an error in Supplementary Fig. 5. In the original Supplementary Fig. 5a, the labels did not properly communicate that all three panels come from the same experiment and have the same control. The following sentence has been added to the end of the legend for Supplementary Fig. 5a: “The data depicted in the three panels originated from the same experiment and as such the control plot is the same in all panels”. The HTML has been updated to include a corrected version of the Supplementary Information

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

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

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

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

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

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.Lister Institute of Preventative Medicine National Institutes of Health (NIH) grant Pfizer ITEN Awar

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

A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis

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.ISSN:2041-172