Differential serine phosphorylation regulates IkappaB-alpha inactivation.
NF-kappaB is a ubiquitous transcription factor involved in the signal transduction mechanisms of the immune response, acute phase reactions, and viral infections. NF-kappaB proteins are retained in the cytoplasm by association with an inhibitor, termed IkappaB. Studies on the regulation of mammalian IkappaB-alpha have revealed that two amino-terminal conserved phosphoserines are the target sites of incoming signals. We report that the corresponding amino-terminal phosphoserines of avian IkappaB-alpha are phosphorylation targets leading to inactivation of IkappaB-alpha upon stimulation. In addition, we show differential roles for these two serines. Mutation of serine 40 to alanine blocks all stimuli tested (TNF-alpha, phorbol ester, and anti-CD3 and anti-CD28), leading to NF-kappaB activation, while mutation of serine 36 to alanine attenuates only certain transduced signals (PMA, TNF-alpha). These novel findings support the hypothesis that the amino-terminal phosphoserine residues of avian IkappaB-alpha differentially mediate NF-kappaB signal transduction pathways and activation by distinct signals, thereby resulting in the activation NF-kappaB.
Chen
C L
CL
Department of Microbiology and Immunology, Department of Cell Biology, Vanderbilt University School of Medicine, 1161 21st Avenue, South Nashville, Tennessee, 37232-2363, USA.
Yull
F E
FE
Kerr
L D
LD
D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001717:Birds / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D017930:Genes, Reporter; D006801:Humans; D020672:I-kappa B Proteins; D019169:Jurkat Cells; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D012694:Serine; D004247:DNA; D013755:Tetradecanoylphorbol Acetate