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26 April 2024 |
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De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling | | Ingrid E Wertz
; Karen M O’Rourke
; Honglin Zhou
; Michael Eby
; L Aravind
; Somasekar Seshagiri
; Ping Wu
; Christian Wiesmann
; Rohan Baker
; David L Boone
; Averil Ma
; Eugene V Koonin
; Vishva M Dixit
; | | Date: |
5 Aug 2004 | | Journal: | Nature, 430 (7000), 694-9 | | 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. | | Source: | PubMed, pmid15258597 doi: 10.1038/nature02794 | | Services: | Forum | Review | Favorites | |
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