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Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation

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单位： [1]Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [2]Interdisciplinary Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [3]Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [4]State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [5]Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [6]Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA. [7]Transfusion Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. [8]F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA. [9]Department of Neurology, Harvard Medical School, Boston, MA, USA. [10]Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [11]Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [12]Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology and Shanghai Research Institute of Stomatology, National Clinical Research Center for Oral Diseases, Shanghai, China. [13]Interdisciplinary Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [14]Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. [15]Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. [16]Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. [17]Harvard Stem Cell Institute, Cambridge, MA, USA. [18]Broad Institute of MIT and Harvard, Cambridge, MA, USA. [19]Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. [20]Howard Hughes Medical Institute, Chevy Chase, MD, USA.

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The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.

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出版当年[2022]版：

大类 | 1 区

生物学

小类 | 1 区细胞生物学

最新[2025]版：

大类 | 1 区

生物学

小类 | 1 区细胞生物学

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出版当年[2021]版：

Q1 CELL BIOLOGY

最新[2024]版：

Q1 CELL BIOLOGY

影响因子： 19.1 最新[2024版] 22.6 最新五年平均 28.213 出版当年[2021版] 28.123 出版当年五年平均 28.824 出版前一年[2020版] 21.3 出版后一年[2022版]

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第一作者单位： [1]Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

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通讯机构： [2]Interdisciplinary Center of Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [3]Department of Cell Biology, Harvard Medical School, Boston, MA, USA.

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