Negative regulation of toll-like receptor signaling by NF-kappaB p50 ubiquitination blockade.
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)-kappaB 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.
Ruaidhrí J
RJ
Carmody
Qingguo
Q
Ruan
Scott
S
Palmer
Brendan
B
Hilliard
Youhai H
YH
Chen
D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002460:Cell Line; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D005260:Female; D006207:Half-Life; D007108:Immune Tolerance; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D008070:Lipopolysaccharides; D052002:NF-kappa B p50 Subunit; D011518:Proto-Oncogene Proteins; C498144:Rela protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D004247:DNA