A20 inhibits NF-kappa B activation downstream of multiple Map3 kinases and interacts with the I kappa B signalosome.
A20, a TNF inducible gene, inhibits TNF-mediated apoptosis as well as NF-kappa B induced by this cytokine. Reporter assay experiments revealed that A20 is a very effective inhibitor of NF-kappa B signaling induced by TRAFs and several Map3 kinases, including NIK, MEKK1, COT, and TAK1. Similarly, the NF-kappa B inducing activity of TAX, an activator of the I kappa B kinase complex, is also abrogated by A20. Inhibition of NF-kappa B is specific as A20 has no effect on TNF-alpha-induced JNK activation. These results suggest that the molecular target of A20 is more distal to the receptor than TRAFs as previously proposed. A20 inhibits NF-kappa B-dependent transcription without a concomitant decrease in nuclear NF-kappa B DNA binding activity or nuclear translocation of p65. This apparent discrepancy between transcriptional readout and gel shift experiments is observed with a variety of stimuli, including expression of IKK beta. Therefore, in addition to the phosphorylation of I kappa B, another signal is needed for transcriptional activation of NF-kappa B. A20 inhibits this non-redundant signal. The observation that A20 associates with IKK alpha and is phosphorylated upon IKK beta co-expression may suggest that A20 interferes with some aspects of signalosome function.
Zetoune
F S
FS
Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Murthy
A R
AR
Shao
Z
Z
Hlaing
T
T
Zeidler
M G
MG
Li
Y
Y
Vincenz
C
C
D021581:Active Transport, Cell Nucleus; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008156:Luciferases / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D010940:Plant Proteins; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D010940:Plant Proteins; D011506:Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D008156:Luciferases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3