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-?B signalling.
- Authors
Wertz, Ingrid E.; O'Rourke, Karen M.; Honglin Zhou; Eby, Michael; Aravind, L.; Seshagiri, Somasekar; Ping Wu; Wiesmann, Christian; Rohan Baker; Boone, David L.; Ma, Averil; Koonin, Eugene V.; Dixit, Vishva M.
- Abstract
NF-?B transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-a and interleukin-1ß. Failure to downregulate NF-?B transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice. A20 is a potent inhibitor of NF-?B signalling, but its mechanism of action is unknown. Here we show that A20 downregulates NF-?B 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-?B 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.
- Subjects
UBIQUITIN; LIGASES; TRANSCRIPTION factors; PROTEINS; TUMOR necrosis factors; CYTOKINES; CELL death
- Publication
Nature, 2004, Vol 430, Issue 7000, p694
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature02794