Ultraviolet light activates NFkappaB through translational inhibition of IkappaBalpha synthesis.
UV light induces a delayed and prolonged (3-20 h) activation of NFkappaB when compared with the immediate and acute (10-90 min) activation of NFkappaB in response to tumor necrosis factor alpha treatment. In the early phase (3-12 h) of NFkappaB activation, UV light reduces inhibitor of NFkappaB (IkappaB) through an IkappaB kinase-independent, but polyubiquitin-dependent, pathway. However, the mechanism for the UV light-induced reduction of IkappaB and activation of NFkappaB is not known. In this report, we show that UV light down-regulates the total amount of IkappaB through decreasing IkappaB mRNA translation. Our data show that UV light inhibits translation of IkappaB in wild-type mouse embryo fibroblasts (MEF(S/S)) and that this inhibition is prevented in MEF(A/A) cells in which the phosphorylation site, Ser-51 in the eukaryotic translation initiation factor 2 alpha-subunit, is replaced with a non-phosphorylatable Ala (S51A). Our data also show that UV light-induced NFkappaB activation is delayed in MEF(A/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 alpha-subunit phosphorylation translationally inhibits new IkappaB synthesis. Without a continuous supply of newly synthesized IkappaB, the existing IkappaB is degraded through a polyubiquitin-dependent proteasomal pathway leading to NFkappaB activation. Based upon our results, we propose a novel mechanism by which UV light regulates early phase NFkappaB activation by means of an ER-stress-induced translational inhibition pathway.
Wu
Shiyong
S
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
Tan
Mingjia
M
Hu
Yuanyuan
Y
Wang
Ju-Lin
JL
Scheuner
Donalyn
D
Kaufman
Randal J
RJ
D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008027:Light; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D013997:Time Factors; D014466:Ultraviolet Rays; D019892:eIF-2 Kinase / Q000378:metabolism
D015852:Eukaryotic Initiation Factor-2; D020672:I-kappa B Proteins; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D012333:RNA, Messenger; D012694:Serine; D019892:eIF-2 Kinase; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse