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.
Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0375, USA.
Ellen L
EL
O'Dea
Jeffrey D
JD
Kearns
Alexander
A
Hoffmann
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