UV as an amplifier rather than inducer of NF-kappaB activity

• Published in: Molecular cell 2008-06, Vol.30 (5), p.632-641
• Main Authors: O'Dea, Ellen L, Kearns, Jeffrey D, Hoffmann, Alexander
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Homeostasis - radiation effects; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; Inflammation - metabolism; Mice; NF-kappa B - metabolism; Protein Biosynthesis - radiation effects; Signal Transduction - radiation effects; Ultraviolet Rays
• ISSN: 1097-4164
• DOI: 10.1016/j.molcel.2008.03.017

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