Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.
Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.
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DOI：
10.1038/s41556-023-01170-4
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发表时间：
2023-07
影响因子：
21.3
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中科院分区：
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低氧诱导因子1α(HIF-1α)的羟基化是介导细胞在低氧条件下适应的经典信号机制。在这里，我们确定RIPK1，一个已知的由肿瘤坏死因子受体1(TNFR1)介导的细胞死亡调节因子，是EGLN1-pVHL的靶标。EGLN1介导的RIPK1羟基化促进RIPK1与pVHL的结合，抑制其在常氧条件下的激活。长时间的低氧通过调节RIPK1K的脯氨酸羟化来促进RIPK1K的激活，而不依赖于肿瘤坏死因子α-TnFR1途径。因此，抑制RIPK1的脯氨酸羟化会促进RIPK1的激活，从而引发细胞死亡和炎症。肝细胞特异性VHL缺乏促进RIPK1依赖的细胞凋亡，从而介导肝脏病理。我们的发现说明了EGLN-pVHL通路在常氧条件下抑制RIPK1激活以促进细胞存活中的关键作用，以及一个模型，即缺氧通过调节其脯氨酸羟化来促进RIPK1的激活，从而在人类疾病中介导细胞死亡和炎症，而不依赖于TNFR1。
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.
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