In humans, ten Toll-like receptor (TLR) paralogues sense molecular components of microbes, initiating the production of cytokine mediators that create the inflammatory response. Using N-ethyl-N-nitrosourea, we induced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer. Here we identify the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam-1. TrifLps2 homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (a cytoplasmic TIR-domain-containing adaptor protein) loci ablates all responses to LPS, indicating that only two signalling pathways emanate from the LPS receptor. However, a Trif-independent cell population is detectable when TrifLps2 mutant macrophages are stimulated with LPS. This reveals that an alternative MyD88-dependent ‘adaptor X’ pathway is present in some, but not all, macrophages, and implies afferent immune specialization.
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We are grateful to S. Akira for providing MyD88-knockout mice for use in these studies; S. Kusumoto for providing synthetic lipid A; C. Galanos for providing highly purified LPS; and O. Haller for discussions. This work was supported by funding from NIH grants and by a grant from DARPA.
The authors declare that they have no competing financial interests.
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Hoebe, K., Du, X., Georgel, P. et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424, 743–748 (2003). https://doi.org/10.1038/nature01889
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