A20 INHIBITS NF-κB ACTIVATION DOWNSTREAM OF MULTIPLE MAP3 KINASES AND INTERACTS WITH THE IκB SIGNALOSOME

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A20, a TNF inducible gene, inhibits TNF-mediated apoptosis as well as NF-κB induced by this cytokine. Reporter assay experiments revealed that A20 is a very effective inhibitor of NF-κB signaling induced by TRAFs and several Map3 kinases, including NIK, MEKK1, COT, and TAK1. Similarly, the NF-κB inducing activity of TAX, an activator of the IκB kinase complex, is also abrogated by A20. Inhibition of NF-κB is specific as A20 has no effect on TNF-α-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-κB-dependent transcription without a concomitant decrease in nuclear NF-κB 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 IKKβ. Therefore, in addition to the phosphorylation of IκB, another signal is needed for transcriptional activation of NF-κB. A20 inhibits this non-redundant signal. The observation that A20 associates with IKKα and is phosphorylated upon IKKβ co-expression may suggest that A20 interferes with some aspects of signalosome function.