De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-κB 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 and Vishva M. Dixit ()
Additional contact information
Ingrid E. Wertz: Genentech Inc.
Karen M. O'Rourke: Genentech Inc.
Honglin Zhou: Genentech Inc.
Michael Eby: Genentech Inc.
L. Aravind: Computational Biology Branch, NCBI, NLM, NIH
Somasekar Seshagiri: Genentech Inc.
Ping Wu: Genentech Inc.
Christian Wiesmann: Genentech Inc.
Rohan Baker: Australian National University
David L. Boone: University of California, San Francisco
Averil Ma: University of California, San Francisco
Eugene V. Koonin: Computational Biology Branch, NCBI, NLM, NIH
Vishva M. Dixit: Genentech Inc.

Nature, 2004, vol. 430, issue 7000, 694-699

Abstract: Abstract NF-κB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-α and interleukin-1β1. Failure to downregulate NF-κB transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice2. A20 is a potent inhibitor of NF-κB signalling, but its mechanism of action is unknown2. 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) family3, removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein (RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex4,5. The carboxy-terminal domain of A20, composed of seven C2/C2 zinc fingers6, 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.

Date: 2004
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DOI: 10.1038/nature02794

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