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 |
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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. |
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ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature02794 |