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

Zhang, Xu, Liu, Wang et al. identify an inhibitory mechanism for RIPK1 kinase through EGLN1/pVHL-mediated proline hydroxylation, which is disrupted upon prolonged hypoxia that activates RIPK1 activity to promote cell death and inflammation. The prolyl hydroxylation of hypoxia-inducible factor 1 & alpha; (HIF-1 & alpha;) 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 TNF & alpha;-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.

Automated summary

Zhang, Xu, Liu, Wang et al. have discovered that the EGLN1/pVHL-mediated proline hydroxylation inhibits the activity of RIPK1 kinase, but this mechanism is disrupted during prolonged hypoxia, leading to the activation of RIPK1 and consequent cell death and inflammation. The proline hydroxylation of HIF-1α mediated by the EGLN-pVHL pathway is a well-known mechanism for cellular adaptation to hypoxia. The study also reveals that RIPK1, a regulator of TNFR1-mediated cell death, is a target of EGLN1-pVHL, and its proline hydroxylation by EGLN1 suppresses its activation under normoxic conditions.