UV as an amplifier rather than inducer of NF-kappaB activity.
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.
O'Dea
Ellen L
EL
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA.
Kearns
Jeffrey D
JD
Hoffmann
Alexander
A
D000818:Animals; D002478:Cells, Cultured; D006706:Homeostasis / Q000528:radiation effects; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects; D014466:Ultraviolet Rays
D020672:I-kappa B Proteins; D016328:NF-kappa B; D051550:I-kappa B Kinase