Mechanism of Hypoxia-Induced NF- B †

NFB activation is a critical component in the transcriptional response to hypoxia. However, the underlying mechanisms that control its activity under these conditions are unknown. Here we report that under hypoxic conditions, I B kinase (IKK) activity is induced through a calcium/calmodulin-dependent kinase 2 (CaMK2)dependent pathway distinct from that for other common inducers of NFB. This process still requires IKK and the IKK kinase TAK1, like that for inflammatory inducers of NFB, but the TAK1-associated proteins TAB1 and TAB2 are not essential. IKK complex activation following hypoxia requires Ubc13 but not the recently identified LUBAC (linear ubiquitin chain assembly complex) ubiquitin conjugation system. In contrast to the action of other NFB inducers, IKK-mediated phosphorylation of I B does not result in its degradation. We show that this results from I B sumoylation by Sumo-2/3 on critical lysine residues, normally required for K-48-linked polyubiquitination. Furthermore, inhibition of specific Sumo proteases is sufficient to release RelA from I B and activate NFB target genes. These results define a novel pathway regulating NFB activation, important to its physiological role in human health and disease.