pVHL mediates K63-linked ubiquitination of IKKβ, leading to IKKβ inactivation

Nuclear factor (NF)-kappa B is a transcription factor that plays an important role in many biological functions. Regulation of NF-kappa B activity is complicated, and ubiquitination is essential for NF-kappa B activation. Hypoxia can activate NF-kappa B. However, the underlying mechanism remains unclear. pVHL is a tumour suppressor and functions as an adaptor of E3-ligase. In this study, we demonstrated that pVHL inhibits NF-kappa B by mediating K63-ubiquitination of IKK beta, which is dependent on oxygen. We found that pVHL mediates K63-linked ubiquitination of IKK beta, which is an upstream regulator of NF-kappa B. The pVHL-mediated K63-ubiquitination of IKK beta prevents TAK1 binding, which leads to the inhibition of IKK beta phosphorylation and NF-kappa B activation. pVHL-mediated K63-ubiquitination of IKK beta is inhibited under hypoxia. DMOG, which is a specific inhibitor of prolyl hydroxylases, also suppresses K63-ubiquitination of IKK beta. Prolyl hydroxylase (PHD) 1 enhances K63-ubiquitination of imp and inhibits IKK beta phosphorylation. These results suggest a novel function for pVHL in mediating K63-linked ubiquitination of IKK beta, which plays a role in the regulation of IKK/NF-kappa B signalling. The results also provide new insight into the mechanism of NF-kappa B activation through hypoxia. (C) 2016 Elsevier Ireland Ltd. All rights reserved.