We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.
- Authors
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
- Abstract
NF-kappaB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1beta. Failure to downregulate NF-kappaB transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice. A20 is a potent inhibitor of NF-kappaB signalling, but its mechanism of action is unknown. Here we show that A20 downregulates NF-kappaB 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, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers, 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-kappaB 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.
- Publication
Nature, 2004, Vol 430, Issue 7000, p694
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature02794