UV as an Amplifier Rather Than Inducer of NF-κB Activity

SummaryInflammatory activation of NF-κB involves the stimulus-induced degradation of the NF-κB-bound inhibitor IκB via the IκB kinase (IKK). In response to UV irradiation, however, the mechanism and function of NF-κB activation remain unclear. Using a combined biochemical, genetic, and computational modeling approach, we delineate a dual requirement for constitutive IKK-dependent and IKK-independent IκB degradation pathways in conjunction with UV-induced translational inhibition. Interestingly, we find that the high homeostatic turnover of IκB in resting cells renders the NF-κB system remarkably resistant to metabolic stresses, but the two degradation pathways critically and differentially tune NF-κB responsiveness to UV. Indeed, in the context of low chronic inflammation that accelerates NF-κB-bound IκB degradation, UV irradiation results in dramatic NF-κB activation. Our work suggests that the human health relevance of NF-κB activation by UV lies with cellular homeostatic states that are associated with pathology rather than with healthy physiology.