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Negative Regulation of Toll-Like Receptor Signaling by NF-B p50 Ubiquitination Blockade
Ruaidhrí J. Carmody,Qingguo Ruan,Scott Palmer,Brendan Hilliard,Youhai H. Chen*
Toll-like receptors (TLRs) trigger the production of inflammatorycytokines and shape adaptive and innate immunity to pathogens.We report the identification of B cell leukemia (Bcl)–3as an essential negative regulator of TLR signaling. By blockingubiquitination of p50, a member of the nuclear factor (NF)-Bfamily, Bcl-3 stabilizes a p50 complex that inhibits gene transcription.As a consequence, Bcl-3–deficient mice and cells werefound to be hypersensitive to TLR activation and unable to controlresponses to lipopolysaccharides. Thus, p50 ubiquitination blockadeby Bcl-3 limits the strength of TLR responses and maintainsinnate immune homeostasis. These findings indicate that thep50 ubiquitination pathway can be selectively targeted to controldeleterious 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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B p50 Ubiquitination Blockade
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. 
