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

Abstract

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

Anti-hypoxic Effect of Polysaccharide Extract of Brown Seaweed Sargassum dentifolium in Tongue Squamous Cell Carcinoma

“…Moreover, exogenous TRAF6 expression is capable to recover all of the cellular hypoxic phenotypes in absence of HIF-1β. These findings elaborated that HIF-1β is an essential regulator of NF-κB ( 37 ). Therefore, the inhibition of HIF-1β by SD3 may provide not only a role in the inhibition of the hypoxia pathway but also a suppression of the NF-κB activation process, a suggestion that needs further investigations.…”

Chronic and Cycling Hypoxia: Drivers of Cancer Chronic Inflammation through HIF-1 and NF-κB Activation: A Review of the Molecular Mechanisms

“…PHD2 and PHD3 also reduce HIF activity by participating in the degradation of HIF-α subunits. Another mechanism is the involvement of HIF-1β in TNF receptor associated factor 6 (TRAF6) expression and therefore in NF-κB activation [ 143 ]. HIF-1α decreases TRAF6 expression, probably by binding HIF-1β into the HIF-1 complex.…”

MicroRNA‑24 protects against myocardial ischemia‑reperfusion injury via the NF‑κB/TNF‑α pathway

“…It has been previously reported that the occurrence of IRI involves a variety of factors, and the damage caused by inflammatory response to cells is an important pathological mechanism (12). NF-κB, as an inflammation marker, is involved in the occurrence of various diseases, such as chronic inflammatory diseases, heart disease and cancer (13,14). NF-κB signaling regulates the immune response, hypoxia response, apoptosis and embryonic development, as well as tumorigenesis and development (12)(13)(14).…”

“…NF-κB, as an inflammation marker, is involved in the occurrence of various diseases, such as chronic inflammatory diseases, heart disease and cancer (13,14). NF-κB signaling regulates the immune response, hypoxia response, apoptosis and embryonic development, as well as tumorigenesis and development (12)(13)(14). TNF-α serves an important role as a proinflammatory cytokine in NF-κB-mediated inflammation (15).…”