Ultraviolet Light Activates NFκB through Translational Inhibition of IκBα Synthesis*

By Shiyong Wu, M. Tan, Yuanyuan Hu, Ju-lin Wang, D. Scheuner, R. Kaufman. Journal of Biological Chemistry, 2004

129 citations recorded by the source corpus.

UV light induces a delayed and prolonged (3–20 h) activation of NFκB when compared with the immediate and acute (10–90 min) activation of NFκB in response to tumor necrosis factor α treatment. In the early phase (3–12 h) of NFκB activation, UV light reduces inhibitor of NFκB (IκB) through an IκB kinase-independent, but polyubiquitin-dependent, pathway. However, the mechanism for the UV light-induced reduction of IκB and activation of NFκB is not known. In this report, we show that UV light down-regulates the total amount of IκB through decreasing IκB mRNA translation. Our data show that UV light inhibits translation of IκB in wild-type mouse embryo fibroblasts (MEFS/S) and that this inhibition is prevented in MEFA/A cells in which the phosphorylation site, Ser-51 in the eukaryotic translation initiation factor 2 α-subunit, is replaced with a non-phosphorylatable Ala (S51A). Our data also show that UV light-induced NFκB activation is delayed in MEFA/A cells and in an MCF-7 cell line that is stably transfected with a trans-dominant negative mutant protein kinase-like endoplasmic reticulum kinase (PERK). These results suggest that UV light-induced eukaryotic translation initiation factor 2 α-subunit phosphorylation translationally inhibits new IκB synthesis. Without a continuous supply of newly synthesized IκB, the existing IκB is degraded through a polyubiquitin-dependent proteasomal pathway leading to NFκB activation. Based upon our results, we propose a novel mechanism by which UV light regulates early phase NFκB activation by means of an ER-stress-induced translational inhibition pathway.

Subfields: Dermatology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fd3391060f981861bdff1236c07dc1cfae89bef8

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In Molecular Biology

1. R. Kaufman
2. D. Ron
3. H. Harding
4. Nahum Sonenberg
5. S. Marciniak
6. G. Hotamışlıgil
7. Yuhong Zhang
8. Phoebe D. Lu

Citations in the corpus

• Translational Repression Mediates Activation of Nuclear Factor Kappa B by Phosphorylated Translation Initiation Factor 2 (2004, result): “We have no explanation for these differences; however, we do note that since the submission of the present study Wu and colleagues have reported that induction of NF-B DNA binding activity in cells exposed to UV light is also associated with eIF2 phosphorylation-dependent repression of IB synthesis ”
• Endoplasmic reticulum stress signaling in disease. (2006, background): “This novel mechanism extends to NF- B activation in response to other stresses, including ultraviolet (UV) irradiation and amino acid deprivation, where GCN2 appears to be the relevant kinase (77, 78, 211).”