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Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade

Science, 3 August 2007
Vol. 317, Issue 5838, p. 675-678
DOI: 10.1126/science.1142953

Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade

  1. Ruaidhrí J. Carmody,
  2. Qingguo Ruan,
  3. Scott Palmer,
  4. Brendan Hilliard,
  5. Youhai H. Chen*
  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  1. * To whom correspondence should be addressed. E-mail: yhc{at}mail.med.upenn.edu

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)-κB 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.

  • Received for publication 23 March 2007.
  • Accepted for publication 27 June 2007.

Citation:

R. J. Carmody, Q. Ruan, S. Palmer, B. Hilliard, and Y. H. Chen, Negative Regulation of Toll-Like Receptor Signaling by NF-κB p50 Ubiquitination Blockade. Science 317, 675-678 (2007).

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