Toll-like receptors (TLRs) exert powerful proinflammatory responses to microbial pathogens, and TLR responses are stringently regulated during infection so that the chronic exposure of cells to microbial products can ultimately lead to a state of hyporesponsiveness. Carmody et al. identify an essential role for the proto-oncogene protein B cell leukemia (Bcl)-3 in negatively regulating TLR signaling in this context. Bcl-3 blocks ubiquitination of the nuclear factor κB subunit p50, which prevents its degradation and allows it to maintain its inhibition of gene transcription in response to TLR signals. This pathway offers a means by which microbial signals can be prevented from overpowering the immune response.
R. J. Carmody, Q. Ruan, S. Palmer, B. Hilliard, Y. H. Chen, Negative regulation of Toll-like receptor signaling by NF-κB p50 ubiquitination blockade. Science 317, 675-678 (2007). [Abstract] [Full Text]