De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB signalling

NF-κB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-α and interleukin-1β 1 . Failure to downregulate NF-κB transcriptional activity results in chronic inflammation and cell death, as observed in A20 -deficient mice 2 . A20 is a potent inhibito...

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Veröffentlicht in:Nature (London) 2004-08, Vol.430 (7000), p.694-699
Hauptverfasser: Wertz, Ingrid E., O'Rourke, Karen M., Zhou, Honglin, Eby, Michael, Aravind, L., Seshagiri, Somasekar, Wu, Ping, Wiesmann, Christian, Baker, Rohan, Boone, David L., Ma, Averil, Koonin, Eugene V., Dixit, Vishva M.
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Sprache:eng
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Zusammenfassung:NF-κB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-α and interleukin-1β 1 . Failure to downregulate NF-κB transcriptional activity results in chronic inflammation and cell death, as observed in A20 -deficient mice 2 . A20 is a potent inhibitor of NF-κB signalling, but its mechanism of action is unknown 2 . Here we show that A20 downregulates NF-κB signalling through the cooperative activity of its two ubiquitin-editing domains. The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family 3 , removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex 4 , 5 . The carboxy-terminal domain of A20, composed of seven C 2 /C 2 zinc fingers 6 , then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Here we define a novel ubiquitin ligase domain and identify two sequential mechanisms by which A20 downregulates NF-κB signalling. We also provide an example of a protein containing separate ubiquitin ligase and DUB domains, both of which participate in mediating a distinct regulatory effect.
ISSN:0028-0836
1476-4687
DOI:10.1038/nature02794