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Science 317 (5838): 675-678

Copyright © 2007 by the American Association for the Advancement of Science

Negative Regulation of Toll-Like Receptor Signaling by NF-{kappa}B p50 Ubiquitination Blockade

Ruaidhrí J. Carmody, Qingguo Ruan, Scott Palmer, Brendan Hilliard, Youhai H. Chen*

Abstract: Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. We report the identification of B cell leukemia (Bcl)–3 as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, a member of the nuclear factor (NF)-{kappa}B family, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3–deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR responses and maintains innate immune homeostasis. These findings indicate that the p50 ubiquitination pathway can be selectively targeted to control deleterious inflammatory diseases.

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: yhc{at}mail.med.upenn.edu

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