Nature Immunology5, 1052 - 1060 (2004)
Published online: 29 August 2004; Corrected online: 12 September 2004 | doi:10.1038/ni1110
There is a Corrigendum (January 2005) associated with this Article.
The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses
David L Boone1, 4, Emre E Turer1, 4, Eric G Lee1, 4, Regina-Celeste Ahmad1, Matthew T Wheeler2, Colleen Tsui3, Paula Hurley1, Marcia Chien1, Sophia Chai1, Osamu Hitotsumatsu1, Elizabeth McNally2, Cecile Pickart3
& Averil Ma1
1
Department of Medicine, University of California at San Francisco, San Francisco, California 94143-0451, USA.
2
Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA.
3
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)−induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor−induced activity of the transcription factor NF-B and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.
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B and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.
