Abstract
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. Trif(Lps2) 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 Trif(Lps2) 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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism*
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Animals
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Antigens, Differentiation / genetics
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Antigens, Differentiation / physiology*
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Escherichia coli / physiology
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Homozygote
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Interferon Type I / metabolism
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Lipopolysaccharides / pharmacology*
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / microbiology
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Macrophages, Peritoneal / virology
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mutation
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Myeloid Differentiation Factor 88
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Phenotype
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Physical Chromosome Mapping
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Receptors, Cell Surface / metabolism
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Receptors, Immunologic / genetics
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Receptors, Immunologic / physiology*
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Sequence Analysis, DNA
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Signal Transduction / drug effects*
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Substrate Specificity
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha / metabolism
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Vaccinia virus / physiology
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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Antigens, Differentiation
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Interferon Type I
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Lipopolysaccharides
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Membrane Glycoproteins
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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Receptors, Cell Surface
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Receptors, Immunologic
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TICAM-1 protein, mouse
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Toll-Like Receptor 3
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Toll-Like Receptor 4
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha