HIF-1β Positively Regulates NF-κB Activity via Direct Control of TRAF6

NF-kappa B signalling is crucial for cellular responses to inflammation but is also associated with the hypoxia response. NF-kappa B and hypoxia inducible factor (HIF) transcription factors possess an intense molecular crosstalk. Although it is known that HIF-1 alpha modulates NF-kappa B transcriptional response, very little is understood regarding how HIF-1 beta contributes to NF-kappa B signalling. Here, we demonstrate that HIF-1 beta is required for full NF-kappa B activation in cells following canonical and non-canonical stimuli. We found that HIF-1 beta specifically controls TRAF6 expression in human cells but also in Drosophila melanogaster. HIF-1 beta binds to the TRAF6 gene and controls its expression independently of HIF-1 alpha. Furthermore, exogenous TRAF6 expression is able to rescue all of the cellular phenotypes observed in the absence of HIF-1 beta. These results indicate that HIF-1 beta is an important regulator of NF-kappa B with consequences for homeostasis and human disease.